NO303733B1 - New hydropyridine derivatives with antithrombotic activity - Google Patents

Abstract

Hydropyridine derivs. of formula (I) and their tautomers and their salts are new. In (I), R1 = H, 1-4C alkyl, halo, 1-4C haloalkyl, OH, 1-4C alkoxy, 1-4C haloalkoxy, 1-4C alkylthio, 1-4C haloalkylthio, amino, 1-5C alkanoyl, 2-5C haloalkanoyl, COOH, 2-5C alkoxycarbonyl, carbamoyl, CN, NO2, 1-4C alkanesulphonyl, 1-4C haloalkanesulphonyl or sulphamoyl; R2 = 1-10C alkanoyl, 2-10C alkanoyl substd. by at least one A, 3-6C alkenoyl opt. substd. by at least one A, 4-8C cycloalkylcarbonyl opt. substd. by at least one A, benzoyl substd. by at least one B or 5,6-dihydro-1,4,2-dioxazin-3-yl; R3 = H, OH, 1-4C alkoxy opt. substd. by at least one C, aralkyloxy, 1-18C alkanoyl, 3-6C alkenoyl, 4-8C cycloalkylcarbonoxy, arylcarbonyloxy, phthalidyloxy, (5-methyl-2-oxo -1,3-dioxolen-4-yl) methoxy, (5-phenyl-2-oxo-1,3 -dioxolen-4-yl)-methoxy, NRaRb, aralkylamino, 1-18C alkanoylamino, 3-6C alkenoylamino, 4-8C cycloalkylcarbonylamino, arylcarbonylamino, 2-5C alkoxycarbonylamino, aralkyloxycarbonylamino, phthalidylamino, (5-methyl-2-oxo -1,3-dioxolen-4-yl) methylamino, (5-phenyl-2-oxo-1,3 -dioxolen-4-yl) methylamino or NO2; Ra,Rb = H or 1-4C alkyl opt. substd. by at least one C; Y = NH, O or S; n = 1-5; A = halo, OH, 1-4C alkoxy or CN; B = 1-4C alkyl, halo or 1-4C alkoxy; C = 1-4C alkoxy, 1-6C alkanoyloxy or arylcarbonyloxy; alkyl contain 1-4C; aryl have 6-10C in a carbocyclic ring opt. substd. by at least one D; D = as R' except H.

Description

The present invention relates to a series of new tetrahydrothieno[3,2-c]pyridine derivatives, as well as furoanalogues of these derivatives, as well as preparations that utilize their antithrombotic activity.

A number of tetrahydropyridine and tetrahydrofuropyridine derivatives are known, and some of these have been reported to have an antithrombotic effect. For example, US patents 4,051,141, 4,075,215, 4,127,580, 4,467,377 and 4,529,596 all mention compounds of this type, although not all of them mention them because of antithrombotic activity. The closest known technique is believed to be US patent 4,051,141, which i.a. mentions 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]-pyridine and US patent no. 4,529,596 as, among other things, mentions 5-(2-chloro-α-methoxycarbonylbenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine.

However, there are many problems with the previously known compounds referred to in the above, especially since many of them require a long time after administration before they manifest their effect. Thus, there is a need for new compounds of this type with improved efficacy and the ability to act more quickly.

According to the present invention, a series of new tetrahydrothieno[3,2-c]pyridine derivatives and furo- and pyrrolo analogues of these derivatives have been produced which have an improved antithrombotic activity.

For the present invention, it is therefore an aim to produce a series of new compounds of this type.

For the present invention, it is a further and more specific purpose to produce such compounds which have antithrombotic activity.

Other purposes and advantages according to the present invention will become apparent in the course of the description.

The invention thus relates to chemical compounds which are characterized by having the formula (I):

in which

R-*- is a hydrogen atom or a halogen atom;

R is an alkanoyl group having from 1 to 10 carbon atoms, a halogen-substituted alkanoyl group having from 2 to 10 carbon atoms, a cycloalkylcarbonyl group having from 4 to 8 carbon atoms, a halogen-substituted cycloalkylcarbonyl group having from 4 to 8 carbon atoms, a halogen-substituted benzoyl group or a 5, 6-dihydro-1,4,2-dioxazin-3-yl group,

R is a hydrogen atom, a hydroxy group, an alkoxy group with from 1 to 4 carbon atoms, an alkanoyloxy group with from 1 to 18 carbon atoms, an alkanoyloxyalkyl group in which the alkanoyl part has from 1 to 6 carbon atoms and the alkoxy part has from 1 to 4 carbon atoms, an alkoxycarbonyloxy group with from 2 to 5 carbon atoms, an amino group, an alkanoylamino group of from 1 to 10 carbon atoms or a nitro group,

Y is an oxygen or sulfur atom,

n is an integer of 1 or 2, and when n is 2, the groups represented by R<1> can be the same or different from each other,

and tautomers thereof, as well as pharmaceutically acceptable salts of the compounds of formula (I) and of the tautomers.

The invention also provides a pharmaceutical preparation for the treatment and prophylaxis of thrombosis or embolisms, comprising an effective inhibitor of platelet aggregation in mixture with a pharmaceutically acceptable carrier or diluent, wherein the inhibitor is at least one compound of the formula (I), or a tautomer or a pharmaceutically acceptable salt thereof.

When the compounds according to the present invention have an amino or hydroxy group in the 2- or 3-position (ie R<3>is an amino or hydroxy group in the 2- or 3-position), they can exist as keto/enol tautomers , i.e.:

wherein Y, R<1>, R^ and n are as defined above, and Z is a group of the formula =NH or an oxygen atom. These tautomers are or are not readily separable, and if separable, they can be separated using methods well known in the art. In any case, the present invention includes both the individual, isolated tautomers, as well as mixtures thereof, and both the isolated tautomers and such mixtures can be used in the preparations and methods according to the present invention. Particular preference is given to tautomers of the formula (Ia).

In the compounds according to the present invention, there is a carbon atom where an asymmetric carbon atom is attached to the group represented by R, and other carbon atoms can be asymmetric, and thus the compounds form optical isomers. Although these are all represented herein by a single molecular formula, the present invention includes both the individual, isolated isomers and mixtures, including racemates thereof. When stereospecific synthesis techniques are used or optically active compounds are used as starting materials, individual isomers can be prepared directly. If a mixture of isomers is prepared, on the other hand, the individual isomers can be obtained using conventional separation techniques.

When the compounds according to the present invention also have one or more carbon-carbon double bonds or one or more disubstituted cycloalkyl moieties, they form cis- and trans-isomers. The present invention includes both the individual, isolated isomers and mixtures thereof.

The compounds according to the present invention can form acid addition salts. There is no particular limitation on the nature of these salts, provided that they are pharmaceutically acceptable if intended for therapeutic use. When they are intended for non-therapeutic applications, for example as intermediates in the production of other and possibly more active compounds, this limitation does not apply either. Examples of such acid addition salts include: Salts with mineral acids, especially hydrohalic acids (such as hydrofluoric acid, hydrobromic acid, hydroiodic acid or hydrochloric acid), nitric acid, carbonic acid, sulfuric acid or phosphoric acid, salts with lower alkylsulfonic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid or -ethanesulfonic acid, salts with arylsulfonic acids, such as benzenesulfonic acid or p-toluenesulfonic acid, and salts with organic carboxylic acids, such as acetic acid, propionic acid, butyric acid, fumaric acid, tartaric acid, oxalic acid, malonic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid or citric acid.

The compounds can also easily form hydrates, and these are also included in the present invention.

When R° is an amino group, the resulting compound can form a complex salt with a metal ion, and such complex salts also form part of the present invention. Examples of such complex salts include salts with calcium chloride, magnesium chloride, zinc chloride, ferric chloride, stannous (IV) chloride and nickel chloride.

Preferred classes of compounds according to the present invention are those compounds with the formula (I) and tautomers and salts thereof, where: (A) R<2> is an alkanoyl group with from 2 to 6 carbon atoms, a halogen-substituted alkanoyl group having from 2 to 6 carbon atoms, a cycloalkylcarbonyl group having from 4 to 7 carbon atoms, a halogen-substituted cycloalkylcarbonyl group having from 4 to 7 carbon atoms, a substituted benzoyl group with at least one fluorine substituent, or a 5,6-dihydro-1,4,2-dioxazin-3-yl group. (B) R 3 denotes a hydrogen atom, an alkoxy group of from 1 to 4 carbon atoms, an alkanoyloxy methoxy group in which the alkanoyl moiety has from 1 to 5 carbon atoms, an alkanoyloxy group of from 1 to 18 carbon atoms, an alkoxycarbonyloxy group of from 2 to 5 carbon atoms, an amino group, an alkanoylamino group with from 1 to 10 carbon atoms. (C) R<1> represents a halogen atom; R2 denotes an alkanoyl group having from 2 to 6 carbon atoms, a halogen-substituted alkanoyl group having from 2 to 6 carbon atoms, a cycloalkylcarbonyl group having from 4 to 7 carbon atoms, a halogen-substituted cycloalkylcarbonyl group having from 4 to 7 carbon atoms, a substituted benzoyl group with at least one fluorine substituent, or a 5,6-dihydro-1,4,2-dioxazin-3-yl group;

R3 denotes a hydrogen atom, a hydroxy group, an alkoxy group with from 1 to 4 carbon atoms, an alkanoyloxymethoxy group in which the alkanoyl part has from 1 to 5 carbon atoms, an alkanoyloxy group with from 1 to 18 carbon atoms, an alkoxycarbonyloxy group with from 2 to 5 carbon atoms,

an amino group or an alkanoylamino group having from 1 to 10 carbon atoms; and

Y denotes an oxygen or sulfur atom.

(D) R<2> denotes an alkanoyl group having from 2 to 6 carbon atoms, a substituted alkanoyl group having from 2 to 6 carbon atoms and which is substituted by at least one fluorine atom, a cycloalkylcarbonyl group having from 4 to 7 carbon atoms or a

substituted cycloalkylcarbonyl group which is substituted with at least one fluorine atom.

(E) R3 denotes a hydrogen atom, a methoxy group, an ethoxy group, a t-butoxy group, an alkanoyloxymethoxy group

wherein the alkanoyl moiety has from 1 to 5 carbon atoms, an alkanoyloxy group of from 1 to 12 carbon atoms, an alkoxycarbonyloxy group of from 2 to 5 carbon atoms, an amino group or a t-butoxycarbonylamino group.

(F) R<1> represents a halogen atom; R2 denotes an alkanoyl group having from 2 to 6 carbon atoms, a halogen-substituted alkanoyl group having from 2 to 6 carbon atoms, a cycloalkylcarbonyl group having from 4 to 7 carbon atoms, a halogen-substituted cycloalkylcarbonyl group having from 4 to 7 carbon atoms, a halogen-substituted benzoyl group with at least one fluorine substituent, or a 5,6-dihydro-1,4,2-dioxazin-3-yl group;

R 3 denotes a hydrogen atom, a methoxy group, a

ethoxy group, a t-butoxy group, an alkanoyloxymethoxy group in which the alkanoyl part has from 1 to 5 carbon atoms, an alkanoyloxy group with from 1 to 12 carbon atoms, an alkoxycarbonyloxy group with from 2 to 5 carbon atoms, an amino group or a t-butoxycarbonylamino group; and

Y denotes an oxygen or sulfur atom.

(G) R 3 denotes a hydrogen atom, a pivaloyloxy methoxy group, an alkanoyloxy group having from 2 to 10 carbon atoms, or an alkoxycarbonyloxy group having from 2 to 5 carbon atoms. (H)R<1> denotes a halogen atom;

R 2 denotes an alkanoyl group having from 2 to 6 carbon atoms, an alkanoyl group having from 2 to 6 carbon atoms and which is substituted with at least one fluorine atom, a cycloalkylcarbonyl group with from 4 to 7 carbon atoms, or a cycloalkylcarbonyl group which is substituted with at least one fluorine atom;

R3 denotes a hydrogen atom, a pivaloyloxymethoxy group, an alkanoyloxy group with from 2 to 10 carbon atoms or an alkoxycarbonyloxy group with from 2 to 5 carbon atoms; and

Y denotes a sulfur atom.

(I) R 2 denotes an acetyl group, a propionyl group, an acetyl group or propionyl group which is substituted by at least one fluorine atom, a cyclopropylcarbonyl group, a cyclobutylcarbonyl group or a cyclopropylcarbonyl or cyclobutylcarbonyl group which is substituted by at least one fluorine atom.

(J) R 3 denotes a hydrogen atom, a pivaloyloxy methoxy group, an alkanoyloxy group with from 2 to 6 carbon atoms or an alkoxycarbonyloxy group with from 2 to 5 carbon atoms.

(K) R<1> represents a fluorine or chlorine atom;

R 2 denotes an acetyl group, a propionyl group, a

acetyl or propionyl group substituted by at least one fluorine atom, a cyclopropylcarbonyl group, a cyclobutylcarbonyl group or a cyclopropylcarbonyl or cyclobutylcarbonyl group substituted by at least one fluorine atom;

R3 denotes a hydrogen atom, a pivaloyloxymethoxy group, an alkanoyloxy group with from 2 to 6 carbon atoms or an alkoxycarbonyloxy group with from 2 to 5 carbon atoms; and

Y denotes a sulfur atom.

The most preferred compounds are compounds

5-(2-fluoro-α-propionylbenzyl)-4,5,6,7-tetrahydrothieno [3, 2-c] pyridine or a pharmaceutically acceptable salt thereof,

5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine or a pharmaceutically acceptable salt thereof,

5-(2-chloro-α-cyclopropylcarbonylbenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine or a pharmaceutically acceptable salt thereof,

2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4, 5, 6, 7-tetrahydrothieno[3,2-c]pyridine or a pharmaceutically acceptable salt thereof,

5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-propionyl-oxy-4, 5, 6,7-tetrahydrothieno[3,2-c]pyridine or a pharmaceutically acceptable salt thereof,

2-butyryloxy-5-(α-cyclopropylcarbonyl-2-fluorobenz-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine or a pharmaceutically acceptable salt thereof, 5-(a -cyclopropylcarbonyl-2-fluorobenzyl)-2-pivaloyloxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine or a pharmaceutically acceptable salt thereof, 2-t-butoxycarbonyloxy-5-(a- cyclopropylcarbonyl - 2 - fluorobenzyl )-4, 5,6,7-tetrahydrothieno[3,2-c]pyridine or a pharmaceutically acceptable salt thereof, 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-pivaloyloc-simethoxy- 4, 5, 6, 7-tetrahydrothieno[3, 2-c]pyridine or a pharmaceutically acceptable salt thereof, 5-(2-chloro-α-cyclopropylcarbonylbenzyl)-2-oxo-2,4, 5, 6, 7,7a-Hexahydrothieno[3,2-c]pyridine or a tautomer thereof or a pharmaceutically acceptable salt thereof, 5-(2-fluoro-a-propionylbenzyl)-2-oxo-2,4,5,6,7 , 7α-hexahydrothieno[3,2-c]pyridine or a tautomer thereof or a pharmaceutically acceptable salt thereof, 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4, 5, 6, 7,7a-hexahydrothieno[3,2-c]pyridine or a tautomer thereof or a pharmaceutically acceptable salt thereof, 5-[a-(2-fluorocyclopropylcarbonyl-2-fluorobenzyl]-2-oxo-2,4,5, 6, 7,7a-hexahydrothieno[3,2-c]pyridine or a tautomer thereof or a pharmaceutically acceptable salt thereof.

The compounds according to the present invention can be prepared using a selection of methods, the general techniques of which are known in the art for the preparation of compounds of this type. For example, they can be prepared by reacting a compound of formula (III):

(in which R i , R 9 and n are as defined above, and X represents a halogen atom, for example a fluorine,

chlorine, bromine or iodine atom, preferably a chlorine or bromine atom) with a compound of formula (IV): (wherein Y is as defined above and Roa is a hydrogen atom or a hydroxy or nitro group) to give a compound with the formula (Ic):

(where r1.R2,R<3a>, n and Y are as defined above).

If required, this compound of formula (Ic) can then be subjected to one or more suitable reactions, which are described in more detail below, in order to

O-a converts the hydroxy or nitro group represented by Roa to any other group represented by R<3> as defined above.

These reactions can be summarized in the following reaction core A:

In the preceding formulas, R<1>, R2, R<3>, R3a, X, Y and n are as defined above.

In step A1 of this reaction scheme, the substituted benzyl halide of formula (III) is reacted with a condensed hydropyridyl compound of formula (IV) to give the compound of formula (Ic). This reaction can be carried out in the presence or absence of an inert solvent (preferably in the presence of an inert solvent) and in the presence or absence of a base (preferably in the presence of a base).

There are no specific limitations on the nature of the base used, and any base known for use in this type of reaction can equally be used here. Examples of suitable bases include: Organic amines, such as triethylamine, tributylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, picoline, lutidine, collidine, 1,8-diazabicyclo[5,4,0]undec-7-ene or 1 , 5-diazabicyclo[4,3,0]non-5-ene, alkali metal alkoxides, such as sodium methoxide, sodium ethoxide or potassium t-butoxide, alkali metal carbonates, such as sodium carbonate or potassium carbonate, and alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide. Among these, the alkali metal carbonates are preferred. The amount of base used is not critical, but generally an amount of base of from an equimolar amount to five times the equimolar amount in relation to the starting material of formula (III) is recommended. When an excess of the starting material of formula (IV) is used, this can also function as a base. Furthermore, this can serve as a solvent if an excess of an organic amine is used as a base.

The reaction is normally and preferably carried out in the presence of a solvent. There is no particular limitation on the type of solvent that should be used, provided that it has no deleterious effect on the reaction or the reagents involved, and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: Ethers, such as diethyl ether, tetrahydrofuran or dioxane, ketones, such as acetone or methyl ethyl ketone, esters, such as ethyl acetate, alcohols, such as methanol, ethanol, propanol, isopropanol or butanol, nitriles, such as acetonitrile , amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone or hexamethyltriamide phosphatamide and sulfoxides, such as dimethylsulfoxide. Among these, the amides or sulfoxides are preferred.

The reaction can take place over a wide temperature range, and the exact reaction temperature is not critical to the invention. Generally speaking, it is convenient to carry out the reaction at a temperature of from 0°C to 200°C (preferably at from about room temperature to 150°C). The reaction time can also vary greatly, depending on many factors, such as the reaction temperature and the nature of the reagents and solvent used. However, a period of from 1 to 24 hours (preferably from 2 to 15 hours) will usually suffice, provided that the reaction is carried out under the preferred conditions outlined above.

After completion of the reaction, the desired compound of formula (Ic) can be recovered from the reaction mixture by conventional means. If, for example, the compound immediately appears in the form of crystals, these can simply be separated out by means of filtration. Alternatively, a suitable extraction procedure comprises: addition of water, if necessary neutralization of the mixture, extraction of the mixture with a water-insoluble organic solvent, drying of the extract and distillation of the solvent. If necessary, the resulting product can be further purified using conventional measures, such as recrystallization or the various chromatographic techniques, for example preparative thin-layer chromatography or column chromatography, especially column chromatography.

In this reaction's optional second step, step A2, the resulting compound of formula (Ic) is converted, if desired, into a compound of formula (I). This reaction may involve any one or more of the following reactions: (1) When R<3a> represents a hydroxy group, alkylation, aralkylation or acylation of this hydroxy group; (2) When R<3a>represents a nitro group, conversion of this nitro group to an amino group; (3) Alkylation, aralkylation or acylation of the resulting amino group as described in

(2) above.

Alkylation, aralkylation or acylation of the hydroxy group in step A2(l) is carried out in an inert solvent and in the presence of a base by a hydroxy compound of formula (Ic) (R<3a> represents a hydroxy group) with a corresponding alkylation, aralkylating or acylating agent, for example an alkyl halide, aralkyl halide, acyl halide or acid anhydride. The nature of this compound obviously depends on the nature of the group which it is desired to introduce into the compound of formula (I). However, examples of suitable compounds are as follows: alkyl halides with from 1 to 4 carbon atoms, such as methyl iodide, ethyl bromide, ethyl iodide, propyl chloride, propyl bromide, butyl chloride or butyl iodide, aralkyl halides with from 7 to 14 carbon atoms, such as benzyl chloride, benzyl bromide, p-methylbenzyl -chloride, p-methoxybenzyl chloride, p-chlorobenzyl chloride, p-fluorobenzyl chloride or naphthylmethyl chloride, alkyl halides with from 1 to 4 carbon atoms which are substituted with an alkoxy group with from 1 to 4 carbon atoms, with an alkanoyloxy group with from 1 to 6 carbon atoms or with an arylcarbonyloxy group with from 7 to 11 carbon atoms, such as methoxymethyl chloride, 1-methoxyethyl chloride, 2-methoxyethyl chloride, 1-methoxypropyl chloride, 1-methoxybutyl chloride, ethoxymethyl chloride, propoxymethyl chloride, butoxymethyl chloride, acetoxymethyl chloride, 1-acetoxyethyl chloride, 2-acetoxyethyl chloride, 1-acetoxypropyl chloride , 1- acetoxybutyl chloride, propionyloxymethyl chloride, butyryloxymethyl chloride, valeryloxymethyl lchloride, pivaloyloxymethyl chloride, benzoyloxymethyl chloride, 1-benzoyloxymethyl chloride, p-methylbenzoyloxymethyl chloride, p-methoxybenzoyloxymethyl chloride, p-chlorobenzoyloxymethyl chloride, p-fluorobenzoyloxymethyl chloride or naphthoyloxymethyl chloride,

alkanoyl halides of from 2 to 18 carbon atoms or a mixed acid anhydride of such a corresponding acid with formic acid, such as acetyl chloride, propionyl chloride, butyryl chloride, butyryl bromide, valeryl chloride, isovaleryl chloride, pivaloyl chloride, hexanoyl chloride, nonanoyl chloride, decanoyl chloride, lauroyl chloride, palmitoyl chloride, stearoyl chloride, mixed formic and acetic anhydride, acetic anhydride, propionic anhydride or butyric anhydride,

alkenoyl chlorides with from 3 to 6 carbon atoms, such as acryloyl chloride, methacryloyl chloride, crotonoyl chloride or 2-hexenoyl chloride,

cycloalkane carbonyl halides with from 3 to 7 carbon atoms in the cycloalkane part, such as cyclopropane carbonyl chloride, cyclobutane carbonyl chloride, cyclopentane carbonyl chloride, cyclohexane carbonyl chloride or cycloheptane carbonyl chloride,

arylcarbonyl halides with from 6 to 10 carbon atoms in the aryl part, such as benzoyl chloride, p-methylbenzoyl chloride, p-methoxybenzoyl chloride, p-chlorobenzoyl chloride, p-fluorobenzoyl chloride or naphthoyl chloride, alkoxycarbonyl halides with from 1 to 4 carbon atoms in the alkoxy part or an alkyl carbonate anhydride with from 1 to 4 carbon atoms in the alkyl part, such as methoxycarbonyl chloride, ethoxycarbonyl chloride, propoxycarbonyl chloride, isopropoxycarbonyl chloride, butoxycarbonyl chloride, t-butoxycarbonyl chloride, dimethyldicarbonate, diethyldicarbonate, dipropyldicarbonate, diisopropyldicarbonate, dibutyldicarbonate or di-tert-butyldicarbonate,

aralkyloxycarbonyl halides with from 7 to 14 carbon atoms in the aralkyl part, such as benzyloxycarbonyl chloride, p-methylbenzyloxycarbonyl chloride, p-methoxybenzyloxycarbonyl chloride, p-chlorobenzyloxycarbonyl chloride, p-fluorobenzyloxycarbonyl chloride or naphthylmethoxycarbonyl chloride,

phthalidyl halides, such as phthalidyl chloride, or substituted methyl halides, such as (5-methyl-or 5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl chloride.

The base used is not critical to the invention, provided that it has no harmful effect on the other parts of the molecule, and any base that is usually used in reactions of this type can equally be used here. Examples of suitable bases include: Alkali metal hydrides, such as lithium hydride or sodium hydride, alkali metal alkoxides, such as sodium methoxide, sodium ethoxide or potassium t-butoxide, alkali metal carbonates, such as sodium carbonate or potassium carbonate, and alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide. Among these, the alkali metal hydrides are preferred.

The reaction is normally and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent used, provided that it has no deleterious effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: Ethers, such as diethyl ether, tetrahydrofuran or dioxane, ketones, such as acetone or methyl ethyl ketone, esters, such as ethyl acetate, nitriles, such as acetonitrile, amides, such as N,N-dimethylformamide, N,N- dimethylacetamide, N-methyl-2-pyrrolidone or hexamethyltriamide phosphatamide, and sulfoxides, such as dimethyl sulfoxide. Among these, the amides are preferred.

The reaction can take place within a wide temperature range, and the exact reaction temperature is not critical to the invention. In general, it is found appropriate to carry out the reaction at a temperature of from -10°C to 100°C (preferably from 0°C to 50°C), although this may vary, depending on the nature of the compound of formula (Ic) and the solvent. The reaction time can also vary greatly, depending on many factors, such as the reaction temperature and the nature of the reagents and the solvent used. However, a period of from 30 minutes to 24 hours (preferably from 1 to 10 hours) will usually be sufficient, provided the reaction is carried out under the preferred conditions outlined above.

The reaction in step A2(2), which comprises conversion of the nitro group represented by R<3a> in the compound of formula (Ic) to an amino group is preferably carried out in an inert solvent and in the presence of an acid, by reaction of a nitro compound i of formula (Ic), wherein R<3a>is a nitro group with a reducing agent, for example a metal powder. Suitable reducing metal powders include iron, tin or zinc powders. Among these, iron or tin powder is preferred.

Suitable acids include: Mineral acids, such as hydrochloric or sulfuric acid, and organic acids, such as acetic acid, trifluoroacetic acid, methanesulfonic acid or p-toluenesulfonic acid. Among these, hydrochloric acid or acetic acid is preferred.

The reaction is normally and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent which should be used, provided that it has no deleterious effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: Water, ethers, such as diethyl ether, tetrahydrofuran or dioxane, alcohols, such as methanol or ethanol, the acid used for the reaction, as mentioned above, or a mixture of two or more of these solvents. Among these, it is preferred to use a mixture of water with an acid.

The reaction can take place over a wide temperature range, and the exact reaction temperature is not critical to the invention. Generally speaking, we find it convenient to

carry out the reaction at a temperature of from -10°C to 100°C (preferably from 0°C to 50°C), although this may vary depending on the nature of the starting material of formula (Ic) and on the solvent used. The reaction time can

also vary greatly, depending on many factors, such as the reaction temperature and the nature of the reagents and solvent used. However, usually a period of from 15 minutes to 20 hours (preferably from 30 minutes to 10 hours) will be sufficient, provided the reaction is carried out under the preferred conditions outlined above. If this reaction is carried out in an organic acid and in the presence of one of the acid anhydrides mentioned later in connection with the reaction in step A2(3), this reaction will produce an aminoacylated compound.

Conversion of the nitro group into an amino group can also be carried out in a manner similar to step C2(4) in reaction scheme C described below, and in this case any nitro group contained in R<1> is simultaneously converted into an amino group.

Alkylation, aralkylation or acylation of the amino group can be carried out by reacting an amino compound of formula (Ic), where R<3>represents an amino group with a corresponding alkyl halide, aralkyl halide, acyl halide or acid anhydride [for example: an alkyl halide with from 1 to 4 carbon atoms, an alkyl halide with from 1 to 4 carbon atoms which is substituted with an alkoxy group with from 1 to 4 carbon atoms, with an alkanoyloxy group with from 1 to 6 carbon atoms or with an arylcarbonyloxy group with from 6 to 10 carbon atoms in the aryl part, an aralkyl halide with from 7 to 14 carbon atoms, an alkanoyl halide with from 2 to 18 carbon atoms or a mixed acid anhydride with a corresponding acid with formic acid, an alkenoyl halide with from 3 to 6 carbon atoms, a cycloalkanecarbonyl halide with from 3 to 7 carbon atoms in the cycloalkane moiety, an arylcarbonyl halide with from 6 to 10 carbon atoms in the aryl part, an alkoxycarbonyl halide with from 1 to 4 carbon atoms in the alkoxy part, e t alkylcarbonic anhydride with from 1 to 4 carbon atoms in the alkyl part, an aralkyloxycarbonyl halide with from 7 to 14 carbon atoms in the aralkyl part, a phthalidyl halide, or a (5-methyl-or 5-phenyl-2-oxo-1,3-dioxolene-4 -yl)methyl halide, all as exemplified above in connection with step A2(l)]. This reaction normally and preferably takes place in an inert solvent and in the presence of a base. If it is desired to produce a monoalkyl-amino compound with from 1 to 4 carbon atoms, we prefer to use approx. an equimolar amount of an alkyl halide having from 1 to 4 carbon atoms with respect to the compound of formula (I). If, on the other hand, the desired compound is a dialkylamino compound with 1 to 4 carbon atoms in each alkyl part, it is preferred to use more than approx. 2 mol of an alkyl halide with from 1 to 4 carbon atoms per mol of compound of formula (I).

The reaction is essentially the same as that used in step Al, and it can be carried out using the reaction conditions, the base and the solvent described above in connection with the reaction in question.

After completion of the reaction or any of the reactions described above, the desired compound can be produced from the reaction mixture by conventional techniques. For example, one suitable recovery method includes: Insoluble material is filtered off, water is added to the filtrate, if necessary, the resulting mixture is neutralized, it is extracted with an organic solvent that cannot be mixed with water, such as ethyl acetate, it is dried and the solvent is distilled off. If necessary, the resulting product can be further purified using conventional techniques, such as recrystallization or the various chromatographic techniques, for example preparative thin-layer chromatography or column chromatography, especially column chromatography.

A salt of the compound of formula (I) can be prepared by conventional techniques, which are well known in the art. For example, the compound of formula (I) is treated with an acid, such as hydrochloric acid or maleic acid, in an inert solvent, such as diethyl ether or diisopropyl ether, and the separate crystals are recovered by filtration.

An optically active compound of formula (I) can be prepared by using a corresponding optically active benzyl halide of formula (II) as starting material, or by optical resolution of a racemic compound of formula (I) using conventional techniques, such as fractionation crystallization or liquid chromatography.

The condensed hydropyridyl compound of formula (IV), which is used as one of the starting materials, is known or can be easily prepared using any known method [for example M. Podesta et al., Eur. J. Med. Chem. - Chim. Ther. 9 (5), 487 - 490 (1974), and Japanese Kokai Patent Application Sho 61-246,186]. Compounds of formula (IV) with a nitro group as the group R<3a> are known or can be prepared as follows: The imino group in a compound corresponding to the compound of formula (IV), but in which the group R<3a> is a hydrogen atom [which can easily is produced using any known method (for example as described in Japanese Kokai patent application Sho 62-103,088)] is protected. The protection reaction can be carried out in a manner similar to that described in step A2(3) of reaction scheme A above. The protecting group can for example be an acyl group, such as an alkanoyl group, with from 1 to 18 carbon atoms, as exemplified above. The protective compound is then allowed to react in an inert solvent (which may for example be a fatty acid, such as acetic acid or propionic acid, or an acid anhydride, such as acetic anhydride or propionic anhydride, or a mixture of two or more thereof) with a nitrating agent (such as fuming nitric acid or anhydrous nitric acid) at a suitable temperature, for example from 0°C to 50°C, during a period of for example from 15 minutes to 5 hours, and it is finally treated with an acid (such as aqueous hydrochloric acid or aqueous sulfuric acid) at a suitable temperature, for example from 20°C to 100°C, for example for a period of from 15 minutes to 5 hours, to remove the protective group.

The compound of formula (III), which is the second starting material, can be easily prepared, for example by means of the process shown below in reaction schemes B, C, D and E.

In these formulas, R<1>, X and n are as defined above.

R<la>is a hydrogen atom, an alkyl group with from 1 to 4 carbon atoms, a halogen atom, a haloalkyl group with from 1 to 4 carbon atoms and at least one halogen atom, a hydroxy group, an alkoxy group with from 1 to 4 carbon atoms, a haloalkyl group with from 1 to 4 carbon atoms and at least one halogen atom, an alkylthio group with from 1 to 4 carbon atoms, a haloalkylthio group with from 1 to 4 carbon atoms and at least one halogen atom, an amino group, a protected alkanoyl group with from 1 to 5 carbon atoms in the alkanoyl part , a protected haloalkanoyl group with from 2 to 5 carbon atoms and at least one halogen atom in the haloalkanoyl part, a carbamoyl group, a nitro group, an alkanesulfonyl group with from 1 to 4 carbon atoms, a haloalkanesulfonyl group with from 1 to 4 carbon atoms and at least one halogen atom, or a sulfamoyl group. That is to say, it is the same groups that R<1> does, except that the cyano, carboxy, as well as alkoxycarbonyl and alkanoyl groups and the haloalkanoyl groups are protected.

R<it»>is a hydrogen atom, an alkyl group with from 1 to 4 carbon atoms, a halogen atom, a haloalkyl group with from 1 to 4 carbon atoms and at least one halogen atom, a protected hydroxy group, an alkoxy group with from 1 to 4 carbon atoms, a halogenoalkyl group with from 1 to 4 carbon atoms and at least one halogen atom, an alkylthio group with from 1 to 4 carbon atoms, a haloalkylthio group with from 1 to 4 carbon atoms and at least one halogen atom, a protected alkanoyl group with from 1 to 5 carbon atoms in the alkanoyl part, a protected haloalkanoyl group with from 2 to 5 carbon atoms and at least one halogen atom in the haloalkanoyl part, a nitro group, an alkanesulfonyl group with from 1 to 4 carbon atoms or a haloalkanesulfonyl group with from 1 to 4 carbon atoms and at least one halogen atom. That is to say, it denotes the same groups as R<1> does, except that the amino-, cyano-, carboxy-, carbamoyl-, sulfamoyl- and alkoxycarbonyl groups, as well as the alkanoyl groups, the haloalkanoyl groups and the hydroxy groups, are protected.

R<lc> are the same groups as defined above for R<1>, except that the alkanoyl group of from 1 to 5 carbon atoms and the haloalkanoyl group of from 2 to 5 carbon atoms are protected.

R<2a> is the same groups as defined above in connection with R<2>, except for the dihydrodioxazinyl group.

R<4> is an alkyl group with from 1 to 4 carbon atoms.

R<5>is a hydrogen atom, an alkyl group having from 1 to 9 carbon atoms, a substituted alkyl group having from 1 to 9 carbon atoms and which is substituted by at least one substituent selected from the group consisting of the substituents A, which are defined above, an alkenyl group having from 2 to 5 carbon atoms, a substituted alkenyl group having from 2 to 5 carbon atoms and which is substituted by at least one substituent selected from the group consisting of the substituents A, which are defined in the preceding, a cycloalkyl group having from 3 to 7 carbon atoms, a substituted cycloalkyl group having from 3 to 7 carbon atoms and which is substituted with at least one substituent selected from the group consisting of the substituent A, which is defined above, or a substituted phenyl group with at least one substituent selected from the group consisting of the substituents B, which is defined above, and provided that any hydroxy group in su the bstituents A are protected. That is to say, it is any of the groups (other than dihydrodioxazinyl groups) defined above in connection with R<2>, but without the terminating carbonyl group.

R<5a> is any of the groups represented by R<5>, except that the hydroxy group of the substituent A need not be protected.

There is no specific limitation on the nature of the protecting group for the alkanoyl group having 1 to 5 carbon atoms or the haloalkanoyl group having from 2 to 5 carbon atoms, and any such group which is usually used for the protection of aldehydes and ketones in the field of organic chemistry. Examples include an acetal or ketal containing a carbonyl moiety as shown in the following formula

wherein R<6> and R<7> are the same or different and each is an alkyl group with from 1 to 4 carbon atoms (such as a methyl, ethyl, propyl, isopropyl or butyl group) or R<6> and R<7 >together form an alkylene group with 2 or 3 carbon atoms (such as an ethylene or tri-methylene group). We prefer an acetal or ketal where R<6> and R<7> are each a methyl or ethyl group, or R<6> and R<7> together form an ethylene or trimethylene group.

The nature of the hydroxy protecting groups that can be used in this reaction is not critical and any hydroxy protecting group that is known to be used for this type of reaction can equally be used here. Examples of such groups include groups derived from the cyclic ethers, such as the tetrahydropyranyl or tetrahydrofuranyl group.

In the reaction core B, a compound with the formula (Illa) is produced. This is a compound of the formula (III), where R<2> is a dihydrodioxazinyl group.

In step B1 of this reaction scheme, a compound of the formula (VI) is prepared by reacting a compound of the formula (V) with hydroxylamine or with a mineral acid salt of hydroxylamine (such as hydrochloric acid or sulfate) in an inert solvent (for example an alcohol, such such as methanol or ethanol) and in the presence of a base (for example an alkali metal alkoxide, such as sodium methoxide, sodium ethoxide or potassium t-butoxide) at a suitable temperature, preferably from 0°C to 150°C (preferably from about room temperature to 100 °C) for a suitable period of time, preferably from 1 to 24 hours (preferably from 2 to 15 hours).

In step B2 of this reaction scheme, a compound with the formula (VII) is prepared by reacting a compound with the formula (VI) with a compound with the formula

(XVIII):

wherein Xa and X13 are the same or different and each is a halogen atom. The reaction is normally and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent to be used, provided that it has no deleterious effect on the reaction or on the reagents involved, and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: Water and alcohols, such as methanol or ethanol. The reaction is also preferably carried out in the presence of a base, the nature of which is also not critical for the present invention. Examples of such bases include: Alkali metal carbonates, such as sodium carbonate or potassium carbonate, and alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide. The reaction can take place over a wide temperature range, and the exact reaction temperature is not critical for the present invention. Generally speaking, we find it convenient to carry out the reaction at a temperature of from 0°C to 200°C (preferably at a temperature of from approx. room temperature

to 150°C). The reaction time can also vary greatly, depending on many factors, in particular the reaction temperature and the nature of the reagents and solvent used. However, a period of from 1 to 24 hours (preferably from 2 to 15 hours) will usually be sufficient, provided the reaction is carried out under the preferred conditions outlined above.

Step B3 of this reaction scheme shall optionally give a compound of the formula (VIII), and may consist of one or more of the following reactions: (1) Removal of the alkanoyl or haloalkanoyl protecting group accommodated in R<la>; (2) Conversion of the halogen atom contained in R<la> into a cyano group; (3) Conversion of the halogen atom accommodated in R<la> into a carboxy group, if desired followed by a conversion of the carboxy group into an alkoxycarbonyl group with from 1 to 4 carbon atoms in the alkoxy part.

In this reaction scheme's step B3(1), the removal of the alkanoyl or haloalkanoyl protecting group can be carried out using conventional techniques which are usually used in the field of organic chemistry. If, for example, the protecting group is an acetal or a ketal, a corresponding compound of the formula (VII) is reacted with an acid (for example a mineral acid, such as hydrochloric, sulfuric or nitric acid, or an organic acid, such as acetic acid, trifluoroacetic acid, methanesulfonic acid or p-toluenesulfonic acid). The reaction is normally and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent which should be used, provided that it has no deleterious effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: Water and alcohols, such as methanol or ethanol. The reaction can take place over a wide temperature range, and the exact reaction temperature is not critical to the invention. Generally speaking, it is convenient to carry out the reaction at a temperature of from 0°C to 100°C (preferably at a temperature of from approx. room temperature

to 50°C). The reaction time can also vary greatly, depending on many factors, in particular on the reaction temperature and the nature of the reagents and the solvent used. However, usually a period of from 10 minutes to 5 hours (preferably from 30 minutes to 2 hours) will be sufficient, provided the reaction is carried out under the preferred conditions outlined above.

Conversion of a halogen atom to a cyano group i

step B3(2) of this reaction scheme is preferably carried out by reacting the corresponding compound with the formula (VII) with a metal cyanide, such as sodium cyanide, potassium cyanide or copper cyanide. The reaction is normally and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent which should be used, provided it has no deleterious effect on the reaction or on the reagents involved,

and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: Amides, such as dimethylformamide or dimethylacetamide, and ethers, such as diethyl ether or tetrahydrofuran. The reaction can take place over a wide temperature range, and the exact reaction temperature is not critical to the invention. Generally speaking, we find it convenient to carry out the reaction at a temperature of from 0°C to 200°C (preferably at a temperature of from approx. room temperature

to 150°C). The time required for the reaction can also vary greatly, depending on many factors, in particular the reaction temperature and the nature of the reagents and the solvent used. However, usually a period of from 1 to 24 hours (preferably from 2 to 15 hours) will be sufficient, provided the reaction is carried out under the preferred conditions outlined above.

Conversion of the halogen atom to a carboxy group in step B3(3) of this reaction scheme is preferably carried out by reacting the corresponding compound with the formula (VII) with magnesium. The reaction is normally and preferably carried out in the presence of a solvent. There is no particular limitation on the nature of the solvent employed, provided that it has no deleterious effect on the reaction or on the reagents involved, and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: Ethers, such as diethyl ether or tetrahydrofuran. The reaction can take place over a wide temperature range, and the exact reaction temperature is not critical to the invention. Generally speaking, we find it convenient to carry out the reaction at a temperature of from 0°C to 150°C (preferably at a temperature of from approximately room temperature to 100°C). The reaction time can also vary greatly, depending on many factors, in particular the reaction temperature and the nature of the reagents and the solvent used. However, usually a period of from 30 minutes to 24 hours (preferably from 1 to 10 hours) will be sufficient, provided the reaction is carried out under the preferred conditions outlined above. The resulting Grignard reagent is then reacted with carbon dioxide gas at a temperature of, for example, from 0°C to 150°C (preferably at a temperature of from about room temperature to 100°C) for a suitable period of time, for example from 30 minutes to 24 hours (preferably from 1 to 10 hours).

Conversion of the resulting carboxy group to an alkoxycarbonyl group having from 1 to 4 carbon atoms can, if desired, be carried out by reacting the corresponding carboxylic acid with an alcohol having from 1 to 4 carbon atoms, such as methanol, ethanol, propanol, isopropanol or butanol, in the presence of acid (for example a mineral acid, such as hydrochloric, sulfuric or nitric acid, or an organic acid, such as acetic, trifluoroacetic, ethanesulfonic or p-toluenesulfonic). The reaction can take place over a wide temperature range, and the exact reaction temperature is not critical to the invention. Generally speaking, it is appropriate to carry out the reaction at a temperature of from 0°C to 100°C (preferably at a temperature of from approximately room temperature to 50°C). The reaction time can also vary greatly, depending on many factors, in particular the reaction temperature and the nature of the reagents and the solvent used. However, usually a period of from 30 minutes to 5 hours (preferably from 1 to 2 hours) will be sufficient, provided the reaction is carried out under the preferred conditions outlined above. Rather than using any additional solvent, this reaction is usually carried out by using as solvent a large excess of the alcohol which has from 1 to 4 carbon atoms, and which is one of the reagents.

In step B4, a compound of the formula (Illa) is prepared by reacting a compound of the formula (VIII) with a haloimide, such as N-chlorosuccimide, N-bromosuccimide or N-iodosuccimide, in the presence of a radical initiator, such as benzoyl peroxide, or in that the compound of formula (VIII) is reacted with a halogen, such as chlorine, bromine or iodine, in an inert solvent (for example a halogenated hydrocarbon, preferably a halogenated aliphatic hydrocarbon, such as methylene chloride, chloroform or carbon tetrachloride). The reaction can take place over a wide temperature range, and the exact reaction temperature is not critical to the invention. Generally speaking, it is convenient to carry out the reaction at a temperature of from 0°C to 100°C (preferably at a temperature of from approximately room temperature to 50°C). The reaction time can also vary greatly, depending on many factors, in particular the reaction temperature and the nature of the reagents and the solvent used. However, usually a period of from 30 minutes to 20 hours (preferably from 1 to 15 hours) will be sufficient, provided the reaction is carried out under the preferred conditions outlined above.

In reaction scheme C, a compound with the formula (Illb) is produced. This is a compound of the formula (III), in which R<2> is replaced by R2<a>, i.e. any of the groups defined above for R<2>, except for a dihydrodioxazinyl group.

In step Cl of this reaction scheme, a compound of formula (X) is prepared by reacting a compound of formula (IX) with magnesium in an inert solvent (for example an ether, such as diethyl ether or tetrahydrofuran), to give a Grignard reagent . The reaction can take place over a wide temperature range, and the exact reaction temperature is not critical to the invention. Generally speaking, it is appropriate to carry out the reaction at a temperature of from 0°C to 150°C (preferably at a temperature of from approximately room temperature to 100°C). The reaction time can also vary greatly, depending on many factors, in particular the reaction temperature and the nature of the reagents and solvent used. However, usually a period of from 30 minutes to 24 hours (preferably from 1 to 10 hours) will be sufficient, provided the reaction is carried out under the preferred conditions outlined above. The resulting Grignard reagent is then reacted with a compound of formula (XIX), (XX) or

(XXI):

wherein R<5>and X are as defined above, R<51-3>is any of the groups defined for R<5>, except a group having a cyano substituent, and R<5c>is any of the groups defined in connection with R<5>, except for a hydrogen atom. The reaction can take place over a wide temperature range, and the exact reaction temperature

perature is not critical to the invention. Generally speaking, it is appropriate to carry out the reaction at a temperature of from 0°C to 150°C (preferably at a temperature of from approximately room temperature to 100°C). The reaction time can also vary greatly, depending on many factors, in particular the reaction temperature and the nature of the reagents and solvent used. However, usually a period of from 30 minutes to 24 hours (preferably from 1 to 10 hours) will be sufficient, provided the reaction is carried out under the preferred conditions outlined above.

Step C2 of reaction scheme C comprises one or more of the following optional reactions: (1) Removal of the alkanoyl or haloalkanoyl protecting group accommodated in R<1*3>, (2) Removal of the hydroxy protecting group accommodated in R <1*3>, r<5>, etc, (3) Conversion of the halogen atom accommodated in R<113> into a cyano group and then optionally into a carbamoyl group, and then optionally into a carboxy-, and finally optionally into a alkoxycarbonyl group with

from 1 to 4 carbon atoms in the alkoxy part,

(4) Conversion of the nitro group contained in R<1*3> into an amino group, and (5) Conversion of the alkylthio group contained in R<113> into a sulfamoyl group.

Removal of the alkanoyl or haloalkanoyl protecting group in step C2(l) and removal of the hydroxy-protecting cyclic ether group in step C2(2) can be carried out in a manner similar to Scheme B step B3(l), as described in the foregoing.

Conversion of the halogen atom to a cyano group in step C2(3) can be carried out in a manner similar to that used in reaction scheme B step B3(2), as described above. In this reaction, it is preferred that a compound of the formula (X) which contains a halogen atom in the substituent of R^ is not used as starting material. If a compound containing a halogen atom in the substituent R<5> is used, conversion of this halogen atom into a cyano group is also possible.

Stepwise conversion of the cyano group into carbamoyl and carboxy groups can be carried out by reacting a corresponding compound of formula (X) with an aqueous mineral acid (such as aqueous sulfuric acid, aqueous hydrochloric acid or aqueous nitric acid). The reaction can take place over a wide temperature range, and the exact reaction temperature is not critical to the invention. Generally speaking, it is appropriate to carry out the reaction at a temperature of from 0°C to 200°C (preferably at a temperature of from approximately room temperature to 100°C). The reaction time can also vary greatly, depending on many factors, in particular the reaction temperature and the nature of the reagents and solvent used. However, usually a period of from 1 to 24 hours (preferably from 2 to 15 hours) will be sufficient, provided the reaction is carried out under the preferred conditions outlined above. In this reaction, by adjusting the acid concentration, it is possible to choose whether the carbamoyl or carboxy compound should appear. For example, the carbamoyl compound will appear when the reaction takes place for approx. 90% sulfuric acid, and then it can be converted into the carboxyl compound by reacting for approx. 60% sulfuric acid.

Conversion of the carboxy group to an alkoxycarbonyl group with from 1 to 4 carbon atoms in the alkoxy part can be carried out in a manner similar to that described in step B3(3) of reaction scheme B, as described above.

Conversion of the nitro group to an amino group in step C2(4) can be carried out by reacting the corresponding compound of formula (X) with hydrogen gas (preferably at from 1 atmosphere to 5 atmospheres) in an inert solvent (for example an alcohol, such as methanol or ethanol) and in the presence of a reducing catalyst (such as Raney nickel, palladium-on-charcoal or platinum oxide). The reaction can take place over a wide temperature range, and the exact reaction temperature is not critical to the invention. Generally speaking, it is appropriate to carry out the reaction at a temperature of from 0°C to 150°C (preferably at a temperature of from room temperature to 100°C). The reaction time can also vary greatly, depending on many factors, in particular the reaction temperature and the nature of the reagents and solvent used. However, usually a period of from 30 minutes to 24 hours (preferably from 1 to 10 hours) will be sufficient, provided the reaction is carried out under the preferred conditions outlined above.

Conversion of the alkylthio group to a sulfamoyl group in step C2(5) can be carried out by reacting a corresponding compound of formula (X) with a halogenating agent (such as chlorine or bromine) in an inert solvent (for example water, an organic acid, such as acetic acid or propionic acid or a mixture of two or more thereof), to give a sulfonyl halide. The reaction can take place over a wide temperature range, and the exact reaction temperature is not critical to the invention. Generally speaking, it is appropriate to carry out the reaction at a temperature of from -10°C to 100°C (preferably at a temperature of from -5°C to 50°C). The reaction time can also vary greatly, depending on many factors, in particular the reaction temperature and the nature of the reagents and solvent used. However, usually a period of from 30 minutes to 24 hours (preferably from 1 to 10 hours) will be sufficient, provided the reaction is carried out under the preferred conditions outlined above. The resulting sulfonyl halide is then reacted with ammonia in an inert solvent (for example water or an alcohol such as methanol or ethanol) for example at from 0°C to 100°C (preferably at room temperature to 50°C) for a suitable period of time, for example from 30 minutes to 24 hours (preferably from 1 to 10 hours).

In step C3 of reaction scheme C, a compound of the formula (IIIb) is prepared by halogenating the compound of the formula (XI) which was prepared in step C2. This reaction is essentially the same as that described in step B4 of reaction scheme B and can be carried out using the same reagents and reaction conditions.

Reaction scheme D provides an alternative route for the preparation of the compound of formula (XI), which is also prepared in reaction scheme C step C2.

In step Dl of reaction scheme D, a compound of the formula (XIII) is prepared by reacting a compound of the formula (XII) with a compound of the formula

(XXII):

wherein R<5a> is as defined above. The reaction is normally and preferably carried out in the presence of a solvent. There is no particular limitation on the type of solvent that should be used, provided that it has no deleterious effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include organic acids, such as acetic acid

or propionic acid. The reaction is also normally and preferably carried out in the presence of a base, for example an ammonium salt of an organic acid, such as an ammonium acetate, ammonium propionate or ammonium benzoate. The reaction can take place over a wide temperature range, and the exact reaction temperature is not critical to the invention. Generally speaking, it is appropriate to carry out the reaction at a temperature of from approx. room temperature to 200°C (preferably at a temperature of from 50°C to 150°C). The reaction time can also vary greatly, depending on many factors, particularly the reaction temperature and the nature of the reagents

and the solvent used. However, usually a period of from 1 to 24 hours (preferably from 2 to 15 hours) will be sufficient, provided the reaction is carried out under the preferred conditions outlined above.

In step D2 of reaction scheme D, a compound of formula (XIV) is prepared by reacting a compound of formula (XIII) with a reducing agent (such as zinc or iron) in an inert solvent (for example an organic acid, such as acetic acid or propionic acid) and in the presence of water. The reaction can take place over a wide temperature range, and the exact reaction temperature is not critical to the invention. Generally speaking, we find it appropriate to carry out the reaction at a temperature of from approx. room temperature to 250°C (preferably at a temperature of from 50°C to 150°C). The reaction time can also vary greatly, depending on many factors, in particular on the reaction temperature and the nature of the reagents and the solvent used. However, usually a period of from 30 minutes to 24 hours (preferably from 1 to 10 hours) will be sufficient, provided the reaction is carried out under the preferred conditions outlined above.

Step D3 of this reaction scheme is optional and comprises removal of the alkanoyl or halalkanoyl protecting group accommodated in R<lc>. The removal reaction is essentially the same reaction as that used in step B3 of reaction scheme B, and it can be carried out using the same reagents and reaction conditions.

Reaction scheme E provides an alternative route for the preparation of a compound of formula (XI), which is also prepared in step C2 of reaction scheme C, when R<2a> in the compound of formula (XI) is a formyl group, i.e. a compound of formula (Xla ).

In step E of the reaction scheme E, a compound of the formula (XVI) is prepared by reacting a compound of the formula (XV) with a reducing agent [for example an aluminum hydride, such as lithium tri(t-butoxy) aluminum hydride or lithium aluminum hydride]. The reaction is normally and preferably carried out in the presence of a solvent. There is no particular limitation on the type of solvent that should be used, provided that it has no deleterious effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include ethers, such as diethyl ether or tetrahydrofuran. The reaction can take place over a wide temperature range, and the exact reaction temperature is not critical to the invention. Generally speaking, it is appropriate to carry out the reaction at a temperature of from -30°C to 50°C (preferably at a temperature of from 0°C to room temperature). The reaction time can also vary greatly, depending on many factors, in particular the reaction temperature and the nature of the reagents and the solvent used. However, usually a period of from 1 to 24 hours (preferably from 2 to 15 hours) will be sufficient, provided that the reaction is carried out under the preferred conditions outlined above.

Step E2 of the reaction scheme E is optional and comprises one or more of the following reactions: (1) Removal of the alkanoyl or haloalkanoyl protecting group accommodated in R<la>, (2) Conversion of the halogen atom accommodated in R<la >to a cyano group, which can then, if desired, be converted into a carboxy group, which finally, if desired, can be converted into an alkoxycarbonyl group.

These reactions are essentially the same as those described above in connection with step C2 of the reaction scheme C, and can be carried out using the same reagents and reaction conditions.

After completion of any of these reactions, the desired compound can be recovered from the reaction mixture by conventional techniques.

For example, any insoluble substance can be filtered from and,

if the reaction solution is acidic or alkaline, the solution is neutralized. The desired product can then be recovered by distilling off the solvent, or by adding water, extracting the resulting mixture with a water-insoluble organic solvent, such as ethyl acetate, drying the extract, and then distilling off the solvent. If necessary, the resulting product can be further purified using conventional techniques, such as recrystallization or the various chromatography techniques, for example preparative thin-layer chromatography or column chromatography, especially column chromatography.

When the desired compound is a carboxylic acid derivative, it can alternatively be recovered from the reaction medium by the following procedure: The reaction solution is made alkaline, the resulting mixture is extracted with a water-insoluble organic solvent, such as ethyl acetate, the aqueous layer is neutralized, the desired compound is extracted with a water-insoluble organic solvent, such as ethyl acetate, the extract is dried, and then the solvent is distilled off.

The compounds of the present invention, which are prepared as described above, can be converted into acid addition salts and/or into complexes with metal ions using methods that are well known in the art.

BIOLOGICAL ACTIVITY

The compounds of formula (I) and their tautomers, salts and complexes according to the present invention have an excellent antithrombotic activity and are therefore very suitable for the prevention and therapy of thrombosis and embolism. These activities are demonstrated by means of the following test examples, which use techniques recognized in the art to produce a model for such activity in humans and other mammals.

Test example 1

Prolongation of bleeding time in mice

Male mice of the ICR strain (supplied by Japan Charles River Inc.) were divided into groups of 10 for the test. A sample of the drug to be tested was suspended in a 5%

(w/v) aqueous solution of gum arabic and administered orally to the mice at a dose of 3 mg/kg for 3 consecutive days, namely 48 hours, 24 hours and 4 hours before the bleeding test. For the test, each of the mice was restrained using conventional apparatus, and the tail was cut off 5 mm from the end. The last 2 cm of the tail was kept submerged in physiological saline which was kept heated at 37°C. The time at which the bleeding was observed to cease within a period of 15 seconds was considered the point at which the bleeding stopped, and the time between the cutting off of the tail and the point at which the bleeding stopped was recorded as the bleeding time. The bleeding time was observed for a maximum of 5 minutes and, although bleeding continued for longer than 5 minutes, the bleeding time was reported as 5 minutes (300 seconds). The results are shown in Table 2. The test was carried out using certain of the compounds according to the present invention, as well as with two previously known compounds.

Each of the compounds according to the present invention is identified in the table by the number assigned to it in the previous table 1 and by the number from the example in the following which illustrates its preparation. The previously known compounds are identified as follows: Compound A: 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, Compound B: 5-(2-chloro-a-methoxycarbonylbenzyl) )-4,5,6,7-tetrahydrothieno[3,2-c]pyridine.

Test example 2

Antithrombotic activity

Female rats of the SD strain (supplied by Japan Charles River Inc.) were divided into groups of 4 for the test. A sample of the drug to be tested was suspended in a 5% (w/v) aqueous solution of gum arabic and administered orally to the rats 4 hours before the test. As a control, a 5% (w/v) aqueous solution of gum arabic was administered to a control group of rats, without any test drug. Platelet aggregation was tested according to the method of P. Lumley and P.P.A. Humphrey [J. Pharmacol. Methods 6, 153-166 (1981)] with a partial modification. A 5.4 ml blood sample was taken from the anaesthetized rat's abdominal aorta in 0.6 ml of 3.8% (w/v) sodium citrate solution which served as an anticoagulant. The resulting citrated blood samples were poured into cuvettes, with 1.2 ml in each cuvette, and agitated (1000 rpm) at 37°C. After preliminary heating for 2 minutes, 0.3 ml of the blood sample was taken from each of the cuvettes, and the platelet count was measured using an automatic blood cell counter (E-4000, Sysmex). This was considered the platelet count before supplementation. 0.9 ml of the blood sample in the cuvette was then mixed with 0.1 ml of 0.05 M adenosine diphosphate (ADP) solution or with 0.1 ml of collagen suspension (0.06 mg/ml), to induce platelet aggregation - miter. Two minutes after the addition of ADP or 4 minutes after the addition of the collagen, 0.3 ml of the blood sample was withdrawn and the platelet count was measured. This was considered the platelet count after the addition. The platelet aggregation rate was calculated from the following equation.

100 X (platelet count before addition) - platelet count after addition)/platelet count before addition.

The inhibitory effect (antithrombotic activity) was calculated as percentage inhibition of the treated groups compared to the control groups. The results are given in table 2.

For therapeutic or prophylactic use, the compounds according to the present invention can be administered alone or in admixture with one or more conventional carriers, diluents or additives. Administration can take place by any convenient route, for example orally or parenterally, and the physical form of the agent is chosen taking into account the intended administration route. The compounds can, for example, be administered in the form of powders, granules, tablets, capsules and injections. The dosage may vary depending on the severity and nature of the disease, as well as the patient's symptoms, age and body weight, as well as the chosen route of administration. In the case of oral administration, however, a dose of from 1 to 1000 mg, preferably from 10 to 500 mg, or, in the case of intravenous administration, a dose of from 0.5 to 500 mg, preferably from 5 to 250 mg will normally be suggested. mg. The compound can be administered as a single or a divided dose, for example from 1 to 3 times a day depending on the symptoms.

The preparation of the compound according to the present invention is further illustrated by the following examples, while the preparation of certain of the starting materials used in these examples is illustrated by means of the following syntheses.

Example 1

5- (2-chloro-g?- trifluoroacetylbenzyl) - 4, 5. 6. 7-tetrahydrothieno\ 3 . 2-cl pyridine - (Compound No. 113) 10 ml of methylene chloride was added to 0.39 g (2.6 mmol) of hydrochloric acid 4,5,6,7-tetrahydrothieno[3,2-c]pyridine and 0.28 g (2.6 mmol) of sodium carbonate, and then a solution of 0.67 g (2.2 mmol) of 2-chloro-α-trifluoroacetylbenzyl bromide in 10 mL of methylene chloride was slowly added to the resulting mixture, with stirring at room temperature. The mixture was then stirred at room temperature for 3 hours. At the end of this period, 200 ml of ethyl acetate was added to the reaction mixture and the organic layer was separated, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting distillation residue was subjected to column chromatography with silica gel, using a 100:4 volumetric mixture of toluene and ethyl acetate as eluent, to give 0.31 g of the title compound as a colorless oil.

IR spectrum (thin film) J^^g cm"1:

1685, 1705.

NMR spectrum (CDCl3) 6 ppm:

2.90 - 3.04 (2H, multiplet),

3.90 (1H, triplet, J = 6.0 Hz),

4.01 (1H, triplet, J = 6.0 Hz),

5.51 (1H, doublet, J = 7.3 Hz),

5.58 (1H, doublet, J = 7.3 Hz),

6.82 (1H, doublet, J = 5.4 Hz),

7.19 (2H, doublet, J = 5.4 Hz),

7.36 - 7.58 (4H, multiplet).

Mass spectrum (Cl, m/z): 360 (M<+>+1).

Here and in the following, "CI" in the mass spectra means "chemical ionization".

Example 2

5- f2- chloro- a -( 5. 6- dihydro- l. 4. 2- dioxazin-3- yl)- benzyl1 - 4, 5. 6. 7- tetrahydrothieno\ 2 , 2- clpyridine and its hydrochloride - ( Connection No. 3)

2(a) By following a procedure similar to that described in Example 1, except that an equivalent amount of 2-chloro-α-(5,6-dihydro-1,4,2-dioxazin-3-yl) - benzyl bromide (prepared as described in synthesis 18) was used instead of 2-chloro-α-trifluoroacetylbenzyl bromide,

the title compound appeared in the form of a colorless oil with a yield of 77%.

NMR spectrum (CDCl3) 6 ppm:

2.77 - 2.94 (4H, multiplet),

3.63 (1H, doublet, J = 14.4 Hz),

3.79 (1H, doublet, J = 14.4 Hz),

3.96 - 4.02 (1H, multiplet),

4.08 - 4.14 (1H, multiplet),

4.27 - 4.32 (1H, multiplet),

4.36 - 4.42 (1H, multiplet),

4, 75 (1H, singlet),

6.70 (1H, doublet, J = 5.4 Hz),

7.07 (1H, doublet, J = 5.4 Hz),

7.20 - 7.90 (4H, multiplet).

Mass spectrum (Cl, m/z): 349 (M<+>+1).

2(b) 2.7 g of the title compound, which was obtained as described in step (a) above, was dissolved in 100 ml of diethyl ether, and hydrogen chloride gas was blown through the resulting solution at room temperature. The crystals that precipitated were collected so that 2.3 g of the hydrochloride of the title compound appeared in the form of a colorless powder, which melted at 104 - 107°C.

Elemental analysis for C17<H1>7C1N202S^3/2^0:

Calculated: C: 49.52%; H: 5.13%; N: 6.80%.

Found: C: 49.81%; H: 4.73%; N: 6.56%.

Example 3

5- f 2- fluoro- a-( 5. 6- dihydro- 1, 4, 2- dioxazin-3- yl)- benzyl1 - 4, 5. 6 ■ 7- tetrahydrothienoT3, 2- clpyridine oa its hydrochloride - ( Compound No. 2)

3(a) By following a procedure similar to that described in Example 1, except that an equivalent amount of 2-fluoro-α-(5,6-dihydro-1,4,2-dioxazin-3-yl) -

benzyl bromide (prepared as described in synthesis 19) was used instead of 2-chloro-α-trifluoroacetylbenzyl bromide, the title compound appeared as a colorless oil with a yield of 50%.

NMR spectrum (CDCl3) 6 ppm:

2.73 - 2.98 (4H, multiplet),

3.63 (1H, doublet, J = 13.8 Hz),

3.79 (1H, doublet, J = 13.8 Hz),

3.95 - 4.18 (2H, multiplet),

4.23 - 4.45 (2H, multiplet),

4, 61 (1H, singlet),

6.70 (1H, doublet, J = 5.4 Hz),

7.09 (1H, doublet, J = 5.4 Hz),

7.20 - 7.80 (4H, multiplet).

Mass spectrum (Cl, m/z): 333 (M<+>+1).

3 (b) The procedure described in example 2 (b) was repeated using the title compound, as it was prepared in step (a) above, so that the hydrochloride of the title compound appeared as a colorless powder, which melted at 108 - 112°C, with a yield of 81%.

Elemental analysis for C17<H>17FN202S^HCl H20:

Calculated: C: 52.78%; H: 5.21%; N: 7.24%.

Found: C: 53.19%; H: 4.99%; N: 7.16%.

Example 4

5-\ 1 . 6-difluoro-a-(5,6-dihydro-l.4,2-dioxazin-3-yl)-benzyl1-4,5.6.7-tetrahydrothieno r3. 2- cl pyridine -

(Connection No. 7)

By following a procedure similar to that described in Example 1, except that an equivalent amount of 2,6-difluoro-α-(5,6-dihydro-1,4,2-dioxazin-3-yl)-benzyl bromide (prepared as described in Synthesis 20) was used in place of 2-chloro-α-trifluoroacetylbenzyl bromide, the title compound appeared as a colorless powder melting at 151-153°C, in a yield of 8%.

NMR spectrum (CDCl3) 6 ppm:

2.81 - 2.93 (4H, multiplet),

3.62 (1H, doublet, J = 14.0 Hz),

3.79 (1H, doublet, J = 14.0 Hz),

4.00 - 4.10 (2H, multiplet),

4.26 - 4.36 (2H, multiplet),

4.59 (1H, singlet),

6.70 (1H, doublet, J = 5.4 Hz),

7.08 (1H, doublet, J = 5.4 Hz),

7.20 - 7.80 (4H, multiplet).

Mass spectrum (Cl, m/z): 351 (M<+>+1).

Elemental analysis for C17<H>1<gF>2<N>2<0>2S:

Calculated: C: 58.27%; H: 4.60%; N: 8.00%.

Found: C: 58.22%; H: 4.61%; N: 7.79%.

Example 5

5-\ 2 - chloro-g- cyclopropylcarbonylbenzyl - 4. 5. 6. 7- tetrahydrothieno f3 . 2-cl pyridine and its sulfate - (Compound No. 60)

5(a) Following a procedure similar to that described in Example 1, except that an equivalent amount of 2-chloro-α-cyclopropylcarbonylbenzyl bromide was used in place of 2-chloro-α-trifluoroacetylbenzyl bromide,

the title compound appeared as a yellow oil with a yield of 66%.

NMR spectrum (CDCl3) 6 ppm:

0.78 - 0.90 (2H, multiplet),

0.96 - 1.06 (2H, multiplet),

2.15 - 2.29 (1H, multiplet),

2.83 - 2.94 (4H, multiplet),

3.56 (1H, doublet, J = 4.3 Hz),

3.72 (1H, doublet, J = 4.3 Hz),

5, 06 (1H, singlet),

6.68 (1H, doublet, J = 4.9 Hz),

7.06 (1H, doublet, J = 4.9 Hz),

7.10 - 7.70 (4H, multiplet).

Mass spectrum (CI, m/z): 332 (M<+>+1), 262.

5(b) A procedure similar to that described in Example 2(b) was repeated, using the title compound as prepared in step (a) above, except that concentrated sulfuric acid was added instead of blowing hydrogen chloride gas through the mixture to obtain the sulfate of the title compound in the form of white crystals, which melted at 184 - 186°C, in a yield of 70%.

Elemental analysis for C18<H>18<C>1N0S#H2S04<:>

Calculated: C: 50.28%; H: 4.69%; N: 3.26%.

Found: C: 50.43%; H: 4.53%; N: 7.87%.

Example 6

5- ( 2- f luor- Qf- propionylbenzyl) - 4. 5, 6, 7- tetrahydrothieno \ 2 , 2 - clpyridine and its maleate - ( Compound No. 19)

6(a) 1.85 g (11.13 mmol) of 1-(2-fluorophenyl)-2-butanone (prepared as described in synthesis 9) was dissolved in 30 ml of carbon tetrachloride and then a solution of 1.78 g of bromine in 15 ml of carbon tetrachloride added dropwise to the resulting

terating solution at room temperature over a period of 30 minutes. The resulting mixture was then stirred at room temperature for 5 hours, after which water was added to the reaction mixture. The reaction mixture was then extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. A crude 2-fluoro-α-propionylbenzyl bromide was obtained from this extract by removing the solvent by evaporation under reduced pressure. 1.95 g (11.13 mmol) of hydrochloric acid 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, 3.38 g (24.45 mmol) of anhydrous potassium carbonate and 30 ml of dimethylformamide were added to the crude product thus obtained, and the resulting mixture was stirred at room temperature for 5 hours. At the end of this period, toluene was added to the reaction mixture, and after the insoluble matter had been removed by filtration, the filtrate was concentrated by evaporation under reduced pressure. The resulting evaporation residue was subjected to silica gel column chromatography, using a 19:1 volumetric mixture of toluene and ethyl acetate as eluent, to give 1.17 g of the title compound as a pale yellow oil.

IR spectrum (thin film) vmax cm<_1>:

1715.

NMR spectrum (CDCl3) 6 ppm:

1.03 (3H, triplet, J = 7.0 Hz),

2.50 (2H, quartet, J = 7.0 Hz),

2.80 - 2.95 (4H, multiplet),

3.53 (1H, doublet, J = 11.0 Hz),

3.63 (1H, doublet, J = 11.0 Hz),

4.75 (1H, singlet),

6.67 (1H, doublet, J = 5.7 Hz),

7.05 (1H, doublet, J = 5.7 Hz),

7.10 - 7.55 (4H, multiplet).

Mass spectrum (CI, m/z): 304 (M<+>+1), 246.

6(b) A procedure similar to that described in Example 2 (b) was repeated, using the title compound prepared as described in step (a) above, except that maleic acid was added instead of blowing hydrogen chloride gas through the reaction mixture, to obtain the maleate of the title compound in the form of a colorless powder, which melted at 101 - 103°C, in a yield of 54%.

Elemental analysis for C17<H>18<F>N0S #C4H404 41/2H20:

Calculated: C: 58.86%; H: 5.41%; N: 3.27%.

Found: C: 59.19%; H: 5.33%; N: 3.19%.

Example 7

5-(cy-acetyl-2-chlorobenzyl)-4,5,6,7-tetrahydrothieno f3,2-clpyridine and its hydrochloride - (Compound No. 10)

7(a) Following a procedure similar to that described in Example 6, except that an equivalent amount of 1-(2-chlorophenyl)-2-propanol (prepared as described in Synthesis 10) was used instead of 1 -(2-fluorophenyl)-2-butanone, the title compound appeared as a pale yellow oil with a yield of 44%.

IR spectrum (thin film) vmax cm"1:

1715.

NMR spectrum (CDCl 3 ) 6 ppm:

2.13 (3H, singlet) ,

2.70 - 2.95 (4H, multiplet),

3.50 (1H, doublet, J = 10.0 Hz),

3.70 (1H, doublet, J = 10.0 Hz),

4, 93 (1H, singlet),

6.65 (1H, doublet, J = 5.7 Hz),

7.05 (1H, doublet, J = 5.7 Hz),

7.10 - 7.75 (4H, multiplet).

Mass spectrum (CI, m/z): 306 (M<+>+1), 262.

7(b) A procedure similar to that described in Example 2(b) was repeated, using the title compound prepared in step (a) above, to obtain the hydrochloride of the title compound in the form of a pale yellow powder, which melted at 98 - 101°C, with a yield of 70%.

Elemental analysis for C16<H>16<C>1N0S HC1 JL/2H20:

Calculated: C: 54.70%; H: 5.16%; N: 3.98%.

Found: C: 55.09%; H: 4.97%; N: 3.80%.

Example 8

5- ( 2- chloro- a?- propionylbenzene - 4. 5. 6. 7- tetrahydrothieno f3 , 2-cTpyridine and its hydrochloride - (Compound no. 20)

8(a) Following a procedure similar to that described in Example 6, except that an equivalent amount of 1-(2-chlorophenyl)-2-butanone (prepared as described in Synthesis 11) was used in place of 1 -(2-fluorophenyl)-2-butanone, the title compound appeared as a pale yellow oil with a yield of 32%.

NMR spectrum (CDCl 3 ) 6 ppm:

1.05 (3H, triplet, J = 6.5 Hz),

2.31 - 2.58 (2H, multiplet),

2.75 - 3.00 (4H, multiplet),

3.48 (1H, doublet, J = 14.5 Hz),

3.68 (1H, doublet, J = 14.5 Hz),

4.97 (1H, singlet),

6.65 (1H, doublet, J = 6.0 Hz),

7.05 (1H, doublet, J = 6.0 Hz),

7.10 - 7.65 (4H, multiplet).

Mass spectrum (Cl, m/z): 320 (M<+>+1).

8(b) A procedure similar to that described in Example 2(b) was repeated, using the title compound prepared in step (a) above, to obtain

obtaining the hydrochloride of the title compound in the form of a pale yellow powder, which melted at 110 - 115°C, with a yield of 25%.

Elemental analysis for<C>17<H>18<C>1N0S HC1 H20:

Calculated: C: 54.55%; H: 5.92%; N: 3.74%.

Found: C: 54.39%; H: 5.59%; N: 3.73%.

Example 9

5-(2-chloro-g-hexanoylbenzyl-4.5.6.7-tetrahydrothieno[3,2-clpyridine - (Compound no. 125)

Following a procedure similar to that described in Example 6, except that an equivalent amount of 1-(2-chlorophenyl)-2-heptanone (prepared as described in Synthesis 12) was used in place of 1-(2- fluorophenyl)-2-butanone, the title compound appeared in the form of a yellow oil with a yield of 10%.

NMR spectrum (CDCl 3 ) 6 ppm:

0.90 (3H, triplet, J = 7.6 Hz),

1.10 - 1.60 (6H, multiplet),

2.40 (2H, triplet, J = 8.0 Hz),

2.75 - 3.00 (4H, multiplet),

3.50 (1H, doublet, J = 14.5 Hz),

3.70 (1H, doublet, J = 14.5 Hz),

5.00 (1H, singlet),

6.65 (1H, doublet, J = 6.0 Hz),

7.05 (1H, doublet, J = 6.0 Hz),

7.10 - 7.60 (4H, multiplet).

Mass spectrum (CI, m/z): 362 (M<+>+1), 262.

Example 10

5-( g- acetvl- 2- fluorobenzyl1- 4. 5. 6. 7- tetrahydrothieno \ 3 . 2 - clpyridine and its maleate - ( Compound No. 9) 10 (a) By following a procedure similar to that which is described in Example 6, except that an equivalent amount of 1-(2-fluorophenyl)-2-propanone was used in place of 1-(2-fluorophenyl)-2-butanone, the title compound was obtained as a pale yellow oil in a yield of 55%.

IR spectrum (thin film) in/^^g cm<-1>:

1715.

NMR spectrum (CDCl3) 6 ppm:

2.18 (3H, singlet),

2.80 - 2.95 (4H, multiplet),

3.55 (1H, doublet, J = 12.0 Hz),

3.65 (1H, doublet, J = 12.0 Hz),

4.72 (1H, singlet),

6.65 (1H, doublet, J = 5.5 Hz),

7.05 (1H, doublet, J = 5.5 Hz),

7.10 - 7.55 (4H, multiplet).

Mass spectrum (CI, m/z): 290 (M<+>+1), 246.

10(b) A procedure similar to that described in Example 2 (b) was repeated, using the title compound as prepared in step (a) above, except that maleic acid was added instead of blowing hydrogen chloride gas through the mixture, to obtain the maleate of the title compound in the form of a pale yellow powder, which melted at 104 - 106°C, in a yield of 61%.

Elemental analysis for C16H16<F>NOS #C4H404 <1/2H20:

Calculated: C: 57.96%; H: 5.10%; N: 3.38%.

Found: C: 58.36%; H: 4.94%; N: 3.39%.

Example 11

5-( g- cyclobutylcarbonyl- 2- fluorobenzyl! - 4, 5. 6. 7- tetrahydrothieno T3 . 2- cl pyridine and its maleate - (Compound No. 106)

11(a) Following a procedure similar to that described in Example 6, except that an equivalent amount of cyclobutyl-2-fluorobenzyl ketone (prepared as described in Synthesis 13) was used in place of 1-(2-fluorophenyl) -2-butanone, the title compound appeared as a pale yellow oil with a yield of 24%.

NMR spectrum (CDCl3) 6 ppm:

1.70 - 2.55 (6H, multiplet),

2.80 - 3.00 (4H, multiplet),

3.50 (1H, doublet, J = 11.0 Hz),

3.62 (1H, doublet, J = 11.0 Hz),

3.70 - 3.90 (1H, multiplet),

4.73 (1H, singlet),

6.65 (1H, doublet, J = 6.0 Hz),

7.05 (1H, doublet, J = 6.0 Hz),

7.10 - 7.50 (4H, multiplet).

Mass spectrum (CI, m/z): 330 (M<+>+1), 246.

11(b) A procedure similar to that described in Example 2(b) was repeated, using the title compound as prepared in step (a) above, except that maleic acid was added instead of blowing hydrogen chloride gas through the mixture, to obtain the maleate of the title compound in the form of a colorless powder, which melted at 99 - 104°C, in a yield of 57%.

Elemental analysis for C^gH-LgFNOS C4H404 ^1/2H20:

Calculated: C: 60.78%; H: 5.54%; N: 3.08%.

Found: C: 60.97%; H: 5.48%; N: 3.94%.

NMR spectrum (CDCl3) 5 ppm:

1.70 - 2.30 (6H, multiplet),

3.10 - 3.30 (4H, multiplet),

3.68 - 3.82 (1H, multiplet),

4.30 (2H, wide singlet),

5.55 (1H, singlet),

6.30 (2H, singlet),

6.72 (1H, doublet, J = 6.5 Hz),

7.20 (1H, doublet, J = 6.5 Hz),

7.25 - 7.60 (4H, multiplet).

Example 12

5-( Qf- cyclopropylcarbonyl- 2- f fluorobenzyl 1 - 4. 5. 6. 7- tetrahydrothieno\ 3 . 2- clpyridine and its hydrochloride - (Compound No. 59)

12(a) Following a procedure similar to that described in Example 6, except that an equivalent amount of cyclopropyl-2-fluorobenzyl ketone (prepared as described in Synthesis 8) was used in place of 1-(2-fluorophenyl) -2-butanone, the title compound appeared as a colorless oil with a yield of 69%.

NMR spectrum (CDCl3) 5 ppm:

0.78 - 0.90 (2H, multiplet),

0.98 - 1.11 (2H, multiplet),

2.22 - 2.34 (1H, multiplet),

2.72 - 2.98 (4H, multiplet),

3.58 (1H, doublet, J = 4.2 Hz),

3.68 (1H, doublet, J = 4.2 Hz),

4.85 (1H, singlet),

6.68 (1H, doublet, J = 4.9 Hz),

7.06 (1H, doublet, J = 4.9 Hz),

7.20 - 7.60 (4H, multiplet).

Mass spectrum (CI, m/z): 316 (M<+>+1), 246.

12(b) A procedure similar to that described in Example 2(b) was repeated, using the title compound as prepared in step (a) above, to obtain the hydrochloride of the title compound in the form of white crystals, which melted at 171 - 173°C, with a yield of 75%.

Elemental analysis for C18<H>18<F>NOS HC1:

Calculated: C: 61.44%; H: 5.44%; N: 3.98%.

Found: C: 61.37%; H: 5.74%; N: 3.85%.

Example 13

5-(a-butyryl-2-fluorobenzyl1-4.5,6,7-tetrahydrothieno f3.2-clpyridine and its maleate - (Compound No. 116)

13(a) By following a procedure similar to that described in Example 6, except that an equivalent amount of 1-(2-fluorophenyl)-2-pentanone (prepared as described in Synthesis 5) was used instead of l -(2-fluorophenyl)-2-butanone, the title compound appeared as a pale yellow oil with a yield of 41%.

NMR spectrum (CDCl3) 5 ppm:

0.82 (3H, triplet),

1.45 - 1.70 (2H, multiplet),

2.41 (2H, triplet, J = 8.0 Hz),

2.75 - 2.95 (4H, multiplet),

3.55 (1H, doublet, J = 13.0 Hz),

3.62 (1H, doublet, J = 13.0 Hz),

4, 75 (1H, singlet),

6.65 (1H, doublet, J = 6.0 Hz),

7.05 (1H, doublet, J = 6.0 Hz),

7.10 - 7.55 (4H, multiplet).

Mass spectrum (Cl, m/z): 318 (M++1), 246.

13 (b) A procedure similar to that described in Example 2 (b) was repeated, using the title compound prepared as described in step (a) above, except that maleic acid was added instead of blowing hydrogen chloride gas through the mixture, to obtain the maleate of the title compound in the form of a colorless powder, which melted at 89 - 90°C, in a yield of 36%.

Elemental analysis for C18H2oFNOSC4<H>4<0>4<:>

Calculated: C: 60.96%; H: 5.58%; N: 3.23%.

Found: C: 60.69%; H: 5.43%; N: 3.01%.

Example 14

5-( 2- f luor- of- valerylbenzyl- 4. 5. 6, 7- tetrahydrothieno f3, 2-clpyridine and its maleate - ( Compound No. 120) 14 (a) By following a procedure similar to that which is described in Example 6, except that an equivalent amount of 1-(2-fluorophenyl)-2-hexanone (prepared as described in Synthesis 6) was used in place of 1-(2-fluorophenyl)-2-butanone, the title compound was obtained in form of a pale yellow oil with a yield of 46%.

NMR spectrum (CDCl3) 8 ppm:

0.83 (3H, triplet, J = 8.0 Hz),

1.12 - 1.35 (2H, multiplet),

1.40 - 1.70 (2H, multiplet),

2.45 (2H, triplet, J = 8.2 Hz),

2.60 - 2.90 (4H, multiplet),

3.52 (1H, doublet, J=14.0 Hz),

3.65 (1H, doublet, J =14.0 Hz),

4.75 (1H, singlet),

6.65 (1H, doublet, J = 6.0 Hz),

7.05 (1H, doublet, J = 6.0 Hz),

7.10 - 7.50 (4H, multiplet).

Mass spectrum (CI, m/z): 332 (M<+>+1), 246.

14(b) A procedure similar to that described in Example 2(b) was repeated, using the title compound prepared as described in step (a) above, except that maleic acid was added instead of blowing hydrogen chloride gas through the mixture, to obtain the maleate of the title compound in the form of a colorless powder, which melted at 92 - 93°C, in a yield of 26%.

Elemental analysis for C19H22FNOSC4H4<0>4<:>

Calculated: C: 61.73%; H: 5.86%; N: 3.13%.

Found: C: 61.38%; H: 5.88%; N: 2.59%.

Example 15

5-(2-Fluoro-g-pivaloylbenzyl-4,5,6,7-tetrahydrothieno\3,2-clpyridine and its hydrochloride - (Compound No. 122)

15(a) By following a procedure similar to that described in Example 6, except that an equivalent amount of 1-(2-fluorophenyl)-3,3-dimethyl-2-butanone (prepared as described in Synthesis 7) was used instead of 1-(2-

fluorophenyl)-2-butanone, the title compound appeared as a pale yellow oil with a yield of 87%.

NMR spectrum (CDCl3) 6 ppm:

1.10 (9H, singlet),

2.74 - 3.00 (4H, multiplet),

3.55 (1H, doublet, J = 15.0 Hz),

3.66 (1H, doublet, J = 15.0 Hz),

5.23 (1H, singlet),

6.63 (1H, doublet, J = 6.0 Hz),

7.03 (1H, doublet, J = 6.0 Hz),

7.10 - 7.55 (4H, multiplet).

Mass spectrum (CI, m/z): 332 (M<+>+1), 246.

15(b) A procedure similar to that described in Example 2(b) was repeated, using the title compound prepared as described in step (a) above, to obtain the hydrochloride of the title compound in the form of a pale yellow powder, which melted at 85 - 90°C, in a yield of 34%.

Elemental analysis for C19<H>22<F>NOSHC1 #H20:

Calculated: C: 59.14%; H: 6.23%; N: 3.63%.

Found: C: 58.99%; H: 6.57%; N: 3.17%.

Example 16

5-r2-chloro-or-(4-fluorobenzoyl)benzyl 1-4,5,6,7-tetrahydrothieno r3,2-clpyridine and its hydrochloride - (Compound no. 149) .

16(a) Following a procedure similar to that described in Example 6, except that an equivalent amount of 2-fluorobenzyl 4-fluorophenyl ketone (prepared as described in Synthesis 22) was used in place of 1-(2-fluorophenyl) )-2-butanone, the title compound appeared as a pale yellow oil with a yield of 58%.

NMR spectrum (CDCl3) 6 ppm:

2.80 - 3.00 (4H, multiplet),

3.63 (1H, doublet, J = 16.0 Hz),

3.80 (1H, doublet, J = 16.0 Hz),

5, 80 (1H, singlet),

6.63 (1H, doublet, J = 6.0 Hz),

7.00 - 7.60 (6H, multiplet),

7.95 - 8.15 (2H, multiplet).

Mass spectrum (CI, m/z): 386 (M<+>+1), 262.

16 (b) A procedure similar to that described in Example 2 (b) was repeated, using the title compound prepared as described in step (a) above, to obtain the hydrochloride of the title compound in the form of a yellow-brown powder, which melted at 121 - 130°C, with a yield of 40%.

Elemental analysis for C21<H>17<C>1FN0S HC1 #1/2H20:

Calculated: C: 58.47%; H: 4.44%; N: 3.25%.

Found: C: 58.25%; H: 4.86%; N: 3.48%.

Example 17

5-( 2- fluoro-g- isobutyrylbenzyl)- 4, 5, 6, 7- tetrahydrothienoF3, 2- cl pyridine and its maleate - (Compound No. 118)

17(a) Following a procedure similar to that described in Example 6, except that an equivalent amount of 2-fluorobenzylisopropylketone (prepared as described in Synthesis 23) was used in place of 1-(2-fluorophenyl)-2 -butanone, the title compound appeared in the form of a yellow oil with a yield of 44%.

NMR spectrum (CDCl3) 5 ppm:

0.95 (3H, doublet, J = 7.0 Hz),

1.10 (3H, doublet, J = 7.0 Hz),

2.60 - 2.80 (1H, multiplet),

2.80 - 2.95 (4H, multiplet),

3.50 (1H, doublet, J = 11.0 Hz),

3.65 (1H, doublet, J = 11.0 Hz),

4.90 (1H, singlet),

6.65 (1H, doublet, J = 5.7 Hz),

7.05 (1H, doublet, J = 5.7 Hz),

7.10 - 7.50 (4H, multiplet).

Mass spectrum (CI, m/z): 318 (M<+>+1), 246.

17(b) A procedure similar to that described in Example 2 (b) was repeated, using the title compound prepared as described in step (a) above, except that maleic acid was added instead of blowing hydrogen chloride gas through the mixture to obtain the maleate of the title compound in the form of a colorless powder, which melted at 96-98°C, in a yield of 42%.

Elemental analysis for C18<H>2o<F>N°S#C4<H>4<0>4<:>

Calculated: C: 61.02%; H: 5.59%; N: 3.23%.

Found: C: 60.74%; H: 5.52%; N: 3.23%.

Example 18

5-(g-cyclopropylcarbonyl-2-fluorobenzyl)-2-nitro-4,5.6.7-tetrahydrothieno\2,2-clpyridine and its hydrochloride -

(Connection no. 175)

18(a) Following a procedure similar to that described in Example 6, except that an equivalent amount of cyclopropyl-2-fluorobenzyl ketone (prepared as described in Synthesis 8) was used in place of 1-(2-fluorophenyl) -2-butanone, and that 2-nitro-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride, (prepared as described in synthesis 24), the title compound appeared as a brown oil in a yield of 72%.

NMR spectrum (CDCl 3 ) 6 ppm:

0.82 - 0.92 (2H, multiplet),

1.01 - 1.11 (2H, multiplet),

2.00 - 2.20 (1H, multiplet),

2.75 - 3.05 (4H, multiplet),

3.61 (2H, singlet),

4.91 (1H, singlet),

7.10 - 7.45 (4H, multiplet),

7.55 (1H, singlet) .

Mass spectrum (CI, m/z): 361 (M<+>+1), 291.

18(b) A procedure similar to that described in Example 2(b) was repeated, using the title compound prepared as described under step (a) above, to obtain the hydrochloride of the title compound in the form of white crystals, which melted at 161 - 168°C, with a yield of 79%.

Elemental analysis for C18H17FN203S HC1:

Calculated: C: 54.47%; H: 4.57%; N: 7.06%.

Found: C: 54.47%; H: 4.63%; N: 6.89%.

Example 19

5-(g-cyclopropylcarbonyl-2-fluorobenzyl)-4.5,6.7-tetrahydrofuroT3. 2- clpyridine and its hydrochloride -

(Connection no. 168)

19(a) By following a procedure similar to that described in Example 12, except that an equivalent amount of 4,5,6,7-tetrahydrofuro[3,2-c] pyridine (prepared as described in Synthesis 25) was used instead of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride, the title compound appeared as a brown oil in a yield of 21%.

NMR spectrum (CDCl3) 6 ppm:

0.75 - 0.95 (2H, multiplet),

0.98 - 1.10 (2H, multiplet),

2.15 - 2.31 (1H, multiplet),

2.65 - 3.05 (4H, multiplet),

3.40 - 3.60 (2H, multiplet),

4, 90 (1H, singlet),

6.15 (1H, doublet, J = 5.0 Hz),

7.05 - 7.55 (5H, muplispot).

Mass spectrum (CI, m/z): 300 (M<+>+1), 230.

19 (b) A procedure similar to that described in Example 2 (b) was repeated, using the title compound prepared as described under step (a) above, to obtain the hydrochloride of the title compound in the form of white crystals, which melted at 154 - 155°C, with a yield of 39%.

Elemental analysis for C18<H>18FN02#HC1:

Calculated: C: 64.38%; H: 5.70%; N: 4.17%.

Found: C: 64.37%; H: 5.80%; N: 4.19%.

Example 20

5-(g-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2. 4. 5 . 6, 7. 7a- hexahydrothienoT3. 2-clpyridine and its hydrochloride - (Compound No. 235)

20(a) By following a procedure similar to that described in Example 12, except that an equivalent amount of 2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine -hydrochloride was used instead of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride, the title compound appeared as a brown oil with a yield of 32%. To bring about crystallization, diisopropyl ether was added to this compound, which gave white crystals, which melted at 123-125°C.

The resulting 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7α-hexahydrothieno[3,2-c]pyridine (compound no. 235) is believed to contain a small amount of the tautomeric 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (compound no. 188), from which it was not separated .

NMR spectrum (CDCl 3 ) 5 ppm:

0.75 - 0.96 (2H, multiplet),

0.99 - 1.14 (2H, multiplet),

1.83 - 2.01 (1H, multiplet),

2.02 - 2.17 (1H, multiplet),

2.25 - 2.45&2.47 - 2.62 (together 2H, each multiplet),

2.85 & 3.10 (together 2H, each doublet, J = 12.0 Hz) ,

3.88 - 4.10&4.03 - 4.16 (together 2H, each multiplet),

4.85&4.89 (total 1H, each singlet),

6.03 & 6.06 (together 1H, each singlet),

7.10 - 7.45 (4H, multiplet).

Mass spectrum (CI, m/z): 332 (M<+>+1), 262.

Elemental analysis for C18H18FN02S:

Calculated: C: 65.23%; H: 5.48%; N: 4.23%.

Found: C: 65.09%; H: 5.55%; N: 4.20%. (b) A procedure similar to that described in Example 2 (b) was repeated, using the title compound prepared as described under step (a) above, to obtain the hydrochloride of the title compound in the form of white crystals, which melted at 104 - 109°C, with a yield of 46%.

Example 21

5-(2-fluoro-a-propionylbenzyl)-2-oxo-2,4.5.6,7,7a-hexa-hydrothieno f3,2-clpyridine and its hydrochloride -

(Connection no. 234)

21(a) Following a procedure similar to that described in Example 20, except that an equivalent amount of 1-(2-fluorophenyl)-2-butanone (which was prepared as described in Synthesis 9) was used instead of cyclopropyl-2-fluorobenzyl ketone, the title compound 1 appeared as a brown oil with a yield of 36%.

The resulting 5-(2-fluoro-α-propionylbenzyl-2-oxo-2,4,5,6,7,7α-hexahydrothieno[3,2-c]pyridine - (compound no. 234) is believed to contain a small amount of the tautomer 5-(2-fluoro-α-propionylbenzyl)-2-hydroxy-4,5,6,7-tetrahydrothieno [3,2-c]pyridine (compound no. 187).

NMR spectrum (CDCl3) 6 ppm:

1.00 (3H, triplet, J = 9.1 Hz),

1.82 - 1.98 (1H, multiplet),

2.25 - 2.50 (4H, multiplet),

2.85 & 3.05 (together 2H, each doublet, J = 14.0 Hz) ,

3.84 - 3.95 & 4.04 - 4.17 (together 2H, each multiplet),

4.72 & 4.76 (together 1H, each singlet),

6.03 Sc 6.07 (total 1H, each singlet),

7.15 - 7.40 (4H, multiplet).

Mass spectrum (CI, m/z): 320 (M<+>+1), 262.

21(b) A procedure similar to that described in Example 2(b) was repeated, using the title compound prepared as described under step (a) above, to obtain the hydrochloride of the title compound in the form of white crystals, which melted at 110 - 115°C, with a yield of 78%.

Example 22

5-(2-fluoro-g-cyclopropylcarbonylbenzyl)-2-oxo-2. 4, 5, 6, 7, 7a- hexahydrothienof3, 2-clpyridine - (Compound No. 233)

Following a procedure similar to that described in Example 5, except that an equivalent amount of 2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine hydrochloride was used instead of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride, a yellow oil appeared. The oil was crystallized from diisopropyl ether to give the title compound as light brown crystals, melting at 119-123°C, in 8% yield.

The resulting 5-(2-chloro-α-cyclopropylcarbonylbenzyl)-2-oxo-2,4,5,6,7,7α-hexahydrothieno[3,2-c]pyridine (compound no. 233) is believed to contain a small amount of the tautomer 5-(2-chloro-α-cyclopropylcarbonylbenzyl)-2-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (Compound No. 186).

NMR spectrum (CDCl3) 6 ppm:

0.75 - 1.10 (4H, multiplet),

1.75 - 2.10 (2H, multiplet),

2.25 - 2.70 (2H, multiplet),

2.90 - 3.30 (2H, multiplet),

3.75 - 4.20 (2H, multiplet),

5.09&5.10 (together 1H, each singlet)

5.98&6.07 (total 1H, each singlet)

7.50 - 7.50 (4H, multiplet).

Mass spectrum (CI, m/z): 348 (M<+>+1), 278.

Example 23

2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4. 5 . 6. 7-tetrahydrothienoF3. 2-clpyridine - (Compound No. 190)

2.6 g (7.8 mmol) 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7α-hexahydrothieno[3,2-c]pyridine (prepared as described in Example 20) was dissolved in a mixture of 10 ml of dimethylformamide and 5 ml of acetic anhydride, and then 0.35 g (8.6 mmol) of a 60% (w/w) dispersion of sodium hydride in mineral oil was added to the resulting solution, under ice cooling. The mixture was then stirred for 20 minutes at the same temperature, after which it was stirred for an additional 3 hours at room temperature. At the end of this period, 300 ml of ethyl acetate was added to the mixture, which was then washed 4 times, each time with 50 ml of a saturated aqueous solution of sodium chloride. The organic layer was separated and dried over anhydrous sodium sulfate and the solvent was removed by evaporation under reduced pressure. The resulting evaporation residue was subjected to silica gel column chromatography, using a 100:3 volumetric

mixture of toluene and ethyl acetate as eluent, to give a yellow oil. This oil was crystallized from diisopropyl ether to give the title compound as white crystals, melting at 120-121.5°C, in a yield of 65%.

IR spectrum (KBr)^a^g cm"<1>:

1758, 1704.

NMR spectrum (CDCl 3 ) 6 ppm:

0.80 - 0.95 (2H, multiplet),

0.99 - 1.16 (2H, multiplet),

2.27 (3H, singlet),

2.21 - 2.34 (1H, multiplet),

2.70 - 2.95 (4H, multiplet),

3.47 (1H, doublet, J = 15.0 Hz),

3.57 (1H, doublet, J = 15.0 Hz),

4, 83 (1H, singlet),

6.27 (1H, singlet),

7.10 - 7.55 (4H, multiplet).

Mass spectrum (CI, m/z): 374 (M<+>+1), 304.

Elemental analysis for C20<H>2<0>FNO3S:

Calculated: C: 64.32%; H: 5.40%; N: 3.75%.

Found: C: 64.46%; H: 5.39%; N: 3.73%.

Example 24

5-(g-cyclopropylcarbonyl-2-fluorobenzyl)-2-propionyl-oxy-4. 5 . 6. 7-tetrahydrothieno\ 3 . 2-cl pyridine - (Compound no.

192)

Following a procedure similar to that described in Example 23, except that an equivalent amount of propionic anhydride was used in place of acetic anhydride, the title compound was obtained as white crystals, melting at 101-102°C, in a yield of 16%.

IR spectrum (KBr) J^a^g cm-1.

1705, 1760.

NMR spectrum (CDCl3) 5 ppm:

0.75 - 0.90 (2H, multiplet),

0.90 - 1.10 (2H, multiplet),

1.21 (3H, triplet, J = 6.7 Hz),

2.15 - 2.37 (1H, multiplet),

2.55 (2H, quartet, J = 6.7 Hz),

2.65 - 2.95 (4H, multiplet),

3.40 - 3.60 (2H, multiplet),

4, 80 (1H, singlet),

6.25 (1H, singlet),

7.05 - 7.55 (4H, multiplet).

Mass spectrum (CI, m/z): 388 (M<+>+1), 318.

Elemental analysis for C21H22FN03S:

Calculated: C: 65.10%; H: 5.72%; N: 3.61%.

Found: C: 64.80%; H: 5.72%; N: 3.61%.

Example 25

2-butyryloxy-5-(Qf-cyclopropylcarbonyl-2-fluorobenzyl)-4. 5. 6. 7- tetrahydrothieno[ 3 , 2 - cl pyridine - (Compound no.

194)

By following a procedure similar to that described in Example 23, except that an equiv

amount of fatty anhydride was used instead of acetic anhydride, the title compound appeared in the form of white crystals, which melted at 84 - 85°C, with a yield of 39%.

IR spectrum (KBr) vmax cm-1:

1756, 1706.

NMR spectrum (CDCl3) 6 ppm:

0.75 - 1.10 (7H, multiplet),

1.65 - 1.85 (2H, multiplet),

2.21 - 2.34 (1H, multiplet),

2.49 (2H, triplet, J = 7.0 Hz),

2.70 - 3.00 (4H, multiplet),

3.52 (2H, broad triplet, J = 16.0 Hz),

4.82 (1H, singlet),

6.25 (1H, singlet),

7.05 - 7.55 (4H, multiplet).

Mass spectrum (CI, m/z): 402 (M<+>+1), 332.

Elemental analysis for C22H24FN03S:

Calculated: C: 65.81%; H: 6.03%; N: 3.49%.

Found: C: 65.92%; H: 5.91%; N:.3.41%.

Example 26

5- (Q?-cyclopropylcarbonyl-2-fluorobenzyl)-2- pivaloylokSY-4 , 5 . 6. 7-tetrahydrothienof3, 2-clpyridine - (Compound no.

196)

By following a procedure similar to that described in Example 23, except that an equiv

amount of pivalic anhydride was used instead of acetic anhydride, the title compound appeared in the form of white crystals, which melted at 91 - 94°C, with a yield of 44%.

IR spectrum (KBr) vmax cm-1:

1749, 1700.

NMR spectrum (CDCl3) 6 ppm:

0.79 - 0.92 (2H, multiplet),

0.98 - 1.09 (2H, multiplet),

1.31 (9H, singlet),

2.23 - 2.36 (1H, multiplet),

2.70 - 2.95 (4H, multiplet),

3.47 (1H, doublet, J = 14.5 Hz),

3.58 (1H, doublet, J = 14.5 Hz),

4.83 (1H, singlet),

6.26 (1H, singlet),

7.05 - 7.55 (4H, multiplet).

Mass spectrum (CI, m/z): 416 (M<+>+1), 346.

Elemental analysis for C^<H->^<g>FNC^S:

Calculated: C: 66.48%; H: 6.31%; N: 3.37%.

Found: C: 66.21%; H: 6.40%; N: 3.38%.

Example 27

5-(g-cyclopropylcarbonyl-2-fluorobenzyl)-2-nonanoyloxy-4. 5. 6, 7-tetrahydrothieno\ 3 . 2-clpyridine - (Compound No. 199)

1.0 g (3.0 mmol) 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7α-hexahydrothieno[3,2-c]pyridine (prepared as described in example 20) was dissolved in 15 ml of dimethylformamide and then 0.18 g (4.5 mmol) 60%

(w/w) dispersion of sodium hydride in mineral oil and 0.82 ml (4.5 mmol) of nonanoyl chloride added, in said order, to the resulting solution, under ice-cooling. The resulting reaction mixture was then stirred at the same temperature for 30 minutes, after which it was stirred at room temperature for an additional 5 hours. 300 ml of ethyl acetate was then added to the mixture, which was then washed with a saturated aqueous solution of sodium bicarbonate and with a saturated aqueous solution of sodium chloride, in that order. The organic layer was separated and dried

over anhydrous sodium sulfate and the solvent was removed by evaporation under reduced pressure. The resulting evaporation residue was subjected to silica gel column chromatography, using a 100:2 volumetric mixture of toluene and ethyl acetate as eluent, to give a yellow oil. The oil was crystallized from petroleum ether to give the title compound as white crystals, which melted at 45-48°C, in a 40% yield.

NMR spectrum (CDCl 3 ) 6 ppm:

0.80 - 1.80 (19H, multiplet),

2.21 - 2.32 (1H, multiplet),

2.53 (2H, triplet, J = 7.5 Hz),

2.70 - 2.95 (4H, multiplet),

3.48 (1H, doublet, J = 15.0 Hz),

3.57 (1H, doublet, J = 15.0 Hz),

4, 84 (1H, singlet),

6.27 (1H, singlet),

7.05 - 7.55 (4H, multiplet).

Mass spectrum (CI, m/z): 472 (M<+>+1), 402.

Elemental analysis for C27H34FN03S:

Calculated: C: 68.76%; H: 7.27%; N: 2.97%.

Found: C: 68.56%; H: 7.49%; N: 2.97%.

Example 28

5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-decanoyloxy-4. 5. 6. 7- tetrahydrothienoF3. 2-cl pyridine and its hydrochloride - (Compound No. 200) 28 (a) Following a procedure similar to that described in Example 27, except that an equivalent amount of decanoyl chloride was used instead of nonanoyl chloride, the title compound was obtained in form a yellow oil, with a yield of 40%.

NMR spectrum (CDCl3) 6 ppm:

0.80 - 1.80 (21H, multiplet),

2.18 - 2.32 (1H, multiplet),

2.52 (2H, triplet, J = 7.5 Hz),

2.70 - 2.97 (4H, multiplet),

3.50 (1H, doublet, J = 14.5 Hz),

3.59 (1H, doublet, J = 14.5 Hz),

4.85 (1H, singlet),

6.26 (1H, singlet),

7.20 - 7.55 (4H, multiplet).

Mass spectrum (CI, m/z): 486 (M<+>+1), 416.

28(b) A procedure similar to that described in Example 2(b) was repeated, using the title compound prepared as described under step (a) above, except that diisopropyl ether was used as the solvent in in place of diethyl ether, to give the hydrochloride of the title compound as yellow crystals, which melted at 62 - 64°C, in 81% yield.

Elemental analysis for C23H3gFN03S HC1:

Calculated: C: 64.41%; H: 7.14%; N: 2.68%.

Found: C: 64.12%; H: 7.05%; N: 2.63%.

Example 29

5-(Qf-cyclopropylcarbonyl-2-fluorobenzyl)-2-palmitoyloxy-4. 5, 6. 7- tetrahydrothieno\ 3 . 2 - clpyridine - (Compound no.

201)

Following a procedure similar to that described in Example 27, except that an equivalent amount of palmitoyl chloride was used in place of nonanoyl chloride, the title compound was obtained as white crystals, melting at 66-68°C, in a yield of 21%.

NMR spectrum (CDCl 3 ) 5 ppm:

0.80 - 1.80 (33H, multiplet),

2.20 - 2.32 (1H, multiplet),

2.51 (2H, triplet, J = 7.5 Hz),

2.70 - 2.95 (4H, multiplet),

3.48 (1H, doublet, J = 15.0 Hz),

3.58 (1H, doublet, J = 15.0 Hz),

4.84 (1H, singlet),

6.26 (1H, singlet),

7.10 - 7.55 (4H, multiplet).

Mass spectrum (CI, m/z): 570 (M<+>+1), 500.

Analysis for C34H4gFN03S:

Calculated: C: 71.66%; H: 8.49%; N: 2.46%.

Found: C: 71.72%; H: 8.62%; N: 2.43%.

Example 30

2 - 1 - butoxycarbonyloxy-5 - (01 - cyclopropylcarbonyl - 2 - fluorobenzyl) - 4, 5. 6, 7- tetrahydrothieno\ 3 , 2- c] pyridine - (Compound No. 203)

Following a procedure similar to that described in Example 23, except that an equivalent amount of di-tert-butyl was used in place of acetic anhydride, the title compound was obtained as white crystals, melting at 98-99°C , with a dividend of 15%.

NMR spectrum (CDCl3) 6 ppm:

0.80 - 0.90 (2H, multiplet),

0.98 - 1.09 (2H, multiplet),

1.55 (9H, singlet),

2.20 - 2.34 (1H, multiplet),

2.70 - 2.95 (4H, multiplet),

3.40 - 3.60 (2H, multiplet),

4.83 (1H, singlet),

6.27 (1H, singlet),

7.07 - 7.52 (4H, multiplet).

Mass spectrum (CI, m/z): 432 (M<+>+1), 362.

Analysis for C23H2gFN04S:

Calculated: C: 64.02%; H: 6.07%; N: 3.25%.

Found: C: 63.57%; H: 6.03%; N: 3;27%.

Example 31

2-amino-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4.5.6,7-tetrahydrothienoT3. 2-cl pyridine - (Compound No. 177) 5 ml of hydrochloric acid was added to 0.4 g of hydrochloric acid 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-nitro-4,5,6,7-tetrahydrothieno [3 , 2 -c] pyridine (prepared as described in Example 18) and then 0.23 g of tin powder was added to the resulting mixture, with stirring, after which the mixture was stirred at room temperature for another 1 hour. 10 ml of water was added to the reaction mixture, which then was extracted with methylene chloride. The methylene chloride layer was removed, and the aqueous layer was concentrated to dryness by evaporation under reduced pressure, and then crystallized from diethyl ether to give a complex of the title compound with stannous chloride, in the form of a pale yellow powder, in 72% yield. .

NMR spectrum (CD3OD) 6 ppm:

0.95 - 1.05 (2H, multiplet),

1.20 - 1.35 (2H, multiplet),

1.85 - 1.99 (1H, multiplet),

3.60 - 3.80 (2H, multiplet),

6.07 (1H, singlet),

7.35 - 7.80 (4H, multiplet).

Example 32

2-Acetylamino-5-(g-cyclopropylcarbonyl-2-fluorobenzyl)-4. 5. 6, 7- tetrahydrothienoT3, 2- clpyridine - (Compound no. 179)

1.85 g (5.13 mmol) 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-nitro-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (prepared as described in Example 18 ) was dissolved in a mixture of 20 ml of acetic acid and 2 ml of acetic anhydride, and then 1.85 g of iron powder was added to the solution, with stirring at room temperature. The mixture was then stirred at the same temperature for 90 minutes. At the end of this period, water and chloroform were added to the reaction mixture, and the mixture was neutralized with sodium carbonate. The inorganic salt thus precipitated was filtered off, the remaining organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined and dried over anhydrous magnesium sulfate and then the solvent was removed by distillation under reduced pressure. The resulting evaporation residue was then subjected to silica gel column chromatography, using a 6

: 4 volumetric mixture of toluene and ethyl acetate as eluent, to give 1.86 g of the title compound. This was crystallized from diisopropyl ether to obtain 1.37 g of the title compound in the form of white crystals, melting at 155-159°C.

NMR spectrum (CDCl 3 ) 6 ppm:

0.78 - 0.94 (2H, multiplet),

0.98 - 1.12 (2H, multiplet),

2.17 (3H, singlet),

2.15 - 2.32 (1H, multiplet),

2.70 - 2.99 (4H, multiplet),

3.50 (1H, doublet, J = 11.4 Hz),

3.60 (1H, doublet, J = 11.4 Hz),

4, 86 (1H, singlet),

6.27 (1H, singlet),

7.10 - 7.55 (4H, multiplet)

7.80 - 8.00 (1H, wide singlet).

Mass spectrum (CI, m/z): 373 (M<+>+1), 303.

Elemental analysis for C2øH2iFN202s:

Calculated: C: 64.49%; H: 5.68%; N: 7.52%.

Found: C: 64.38%; H: 5.50%; N: 7.38%.

Example 33

2-Butyrylamino-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4. 5, 6, 7-tetrahydrothieno\ 3 . 2-clpyridine - (Compound no.

181)

By following a procedure similar to that described in Example 32, except that equivalent amounts of butyric acid and butyric anhydride were used instead of acetic acid and acetic anhydride, the title compound appeared as white crystals, melting at 154-157°C, with a yield of 61%.

NMR spectrum (CDCl 3 ) 6 ppm:

0.78 - 0.94 (2H, multiplet),

0.90 - 1.10 (5H, multiplet),

1.65 - 1.82 (2H, multiplet),

2.21 - 2.39 (3H, multiplet),

2.69 - 2.95 (4H, multiplet),

3.47 (1H, doublet, J = 11.4 Hz),

3.56 (1H, doublet, J = 11.4 Hz),

4, 81 (1H, singlet),

6.25 (1H, singlet),

7.10 - 7.60 (4H, multiplet),

7.70 (1H, singlet).

Mass spectrum (CI, m/z): 401 (M<+>+1), 331.

Analysis for C22<H2>5<FN>2°2S:

Calculated: C: 65.97%; H: 6.29%; N: 6.99%.

Found: C: 65.95%; H: 6.36%; N: 6.95%.

Example 34

Optically active 5-( oi - cyclopropylcarbonyl- 2- fluorobenzyl) - 4. 5. 6. 7- tetrahydrothieno\ 3 . 2- clpyridine - ( Compound No. 591

0.3 g of 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (prepared as described in Example 12) was resolved into fractions by liquid chromatography [ column: DAICEL CHIRALPAC AD (trademark), 1 x 25 cm); eluent: a 1000 : 40 : 1 volumetric mixture of hexane, isopropanol and diethylamine, column temperature: 35°C, flow rate: 4 ml/minute], to obtain an optically active isomer A [retention time: 8.3 minutes, specific rotation angle [a]§5 : -109.4° (C = 1.80, CHCI3)] and an isomer B [retention time: 9.9 minutes, specific rotation angle [a]<g>5 : +100.1° ( C = 1.90, CHCl 3 )].

Isomers A and B were separately dissolved in diethyl ether and then hydrogen chloride gas was allowed to act on the resulting solutions to obtain 0.13 g and 0.12 g of respectively. isomer A and isomer B hydrochlorides, in the form of white crystals.

Isomer A hydrochloride

Melting point: 106 - 110°C.

Elemental analysis for C18<H>18<F>NOSHC1^3/4H20:

Calculated: C: 59.17%, H: 5.65%; N: 3.83%.

Found: C: 59.06%; H: 5.74%; N: 3.90%.

Isomer B hydrochloride

Melting point: 105 - 110°C.

Elementary analysis for

Calculated: C18<H>18<F>NOS HC1 l/2H20<:>

C: 59.91%, H: 5<*>.59%; N: 3.88%.

Found: C: 59.80%; H: 5.84%; N: 3.79%.

Example 35

5- (of- cyclopropylcarbonyl- 2- fluorobenzyl)- 2- pivaloyloxymeth-oxy- 4. 5. 6, 7- tetrahydrothienoT3. 2-cl pyridine - (Compound No. 207)

1.0 g (3.0 mmol) 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7α-hexahydrothieno[3,2-c]pyridine (prepared as described in example 20) was dissolved in 20 ml of dimethylformamide, and then 100 mg (0.6 mmol) of potassium iodide and 0.13 g (3.3 mmol) of a 60% dispersion of sodium hydride in mineral oil were added to the solution at room temperature. The mixture was then stirred at the same temperature for 10 minutes. At the end of this time, a solution of 0.43 mL (3.0 mmol) of pivaloyloxymethyl chloride in 5 mL of dimethylformamide was added dropwise to the resulting mixture over a period of 10 minutes, and the resulting mixture was stirred at room temperature for 30

minutes. 300 ml of ethyl acetate was then added to the reaction mixture and the mixture was washed three times, each time with 50 ml of saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by evaporation under reduced pressure. The resulting evaporation residue was subjected to silica gel column chromatography, using a 100:3 volumetric mixture of toluene and ethyl acetate as eluent, to give the title compound as a colorless oil in 15% yield.

IR spectrum (thin film) v^^s cm"1:

1715, 1702.

NMR spectrum (CDCl 3 ) 5 ppm:

0.79 - 0.93 (2H, multiplet),

0.99 - 1.14 (2H, multiplet),

1.22 (9H, singlet),

2.18 - 2.31 (1H, multiplet),

2.65 - 2.95 (4H, multiplet),

3.44 (1H, doublet, J = 15.5 Hz),

3.55 (1H, doublet, J = 15.5 Hz),

4, 84 (1H, singlet),

5.57 (1H, singlet),

6, 04 (1H, singlet),

7.05 - 7.50 (4H, multiplet).

Mass spectrum (CI, m/z): 446 (M<+>+1), 376.

Example 36

5-(of-cyclopropylcarbonyl-2-fluorobenzyl)-2-methoxy-4,5.6.7-tetrahydrothieno\3. 2 - cl pyridine and its hydrochloride - (Compound No. 210)

36(a) By following a procedure similar to that described in Example 35, except that an equivalent amount of methyl iodide was used in place of pivaloyloxy-

methyl chloride and potassium iodide, to give the title compound as a yellow oil, in 45% yield.

NMR spectrum (CDCl3) <5 ppm:

0.80 - 0.92 (2H, multiplet),

1.00 - 1.10 (2H, multiplet),

2.20 - 2.36 (1H, multiplet),

2.65 - 2.96 (4H, multiplet),

3.42 (1H, doublet, J = 14.5 Hz),

3.55 (1H, doublet, J = 14.5 Hz),

3.80 (3H, singlet),

4.82 (1H, singlet),

5.80 (1H, singlet),

7.10 - 7.60 (4H, multiplet).

Mass spectrum (CI, m/z): 346 (M<+>+1), 276.

36(b) By following a procedure similar to that described in Example 2(b), using all of the title compound prepared as described under step (a) above, the hydrochloride of the title compound was obtained in the form of white crystals, which melted at 102 - 106°C, with a yield of 78%.

Elemental analysis for Cig<H>20<F>NOS^HCl l/ 2H20:

Calculated: C: 5 8.38%, H: 5.67%; N: 3.58%.

Found: C: 58.08%; H: 5.77%; N: 3.53%.

Example 37

5- \oi - (2-fluorocyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2. 4. 5. 6, 7, 7a- hexahydrothienoT3. 2-clpyridine - (Compound No. 275)

By following a procedure similar to that described in Example 1, except that equivalent amounts of 2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine and 2-fluorocyclopropylcarbonyl )benzyl bromide (as described in synthesis 27) was used instead of hydrochloric acid 4,5,6,7-tetrahydrothieno[3, 2-c]pyridine and 2-chloro-α-trifluoroacetylbenzyl bromide, the title compound appeared as a yellow oil, with a dividend of 31%.

The resulting 5-[α-(2-fluorocyclopropylcarbonyl-2-fluorobenzyl]-2-oxo-2,4,5,6,7,7α-hexahydrothieno[3,2-c]-pyridine (compound no. 275) is assumed to contain a small amount of the tautomer 5-[α-(2-fluorocyclopropylcarbonyl-2-fluorobenzyl]-2-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]-pyridine (Compound No. 274) , from which it was not separated.

IR spectrum (thin film) v^^g cm"1:

1680.

NMR spectrum (CDCl 3 ) 6 ppm:

1.48 - 1.55 (2H, multiplet),

1.85 - 2.01 (1H, multiplet),

2.30 - 2.51 (2H, multiplet),

2.53 - 2.90 (1H, multiplet),

3.00 - 3.20 (2H, multiplet),

3.83 - 4.01 & 4.03 - 4.18 (together 2H, each multiplet),

4.46 - 4.60 & 4.79 - 4.29 (together 2H, each multiplet),

6.05 & 6.09 (together 1H, each singlet),

7.10 - 7.45 (4H, multiplet).

Mass spectrum (CI, m/z): 350 (M<+>+1), 262.

Synthesis 1

3-(2-chlorobenzyl)-5.6-dihydro-1,4,2-dioxazine

A solution of 5.0 (29.3 mmol) of o-chlorophenylacetic acid and 0.3 g of p-toluenesulfonic acid monohydrate in 50 ml of methanol was heated under reflux for 6 hours. At the end of this period, 3.1 g (44 mmol) of hydrochloric acid hydroxylamine was added to the reaction mixture, followed by 2.1 g of sodium methoxide. The resulting reaction mixture was then heated under reflux for 10 hours. 14.2 g (103 mmol) of sodium carbonate and 5.1 ml of 1,2-dibromoethane were then added to the resulting reaction mixture, followed by 15 ml of water. The reaction mixture was then heated under reflux for an additional 10 hours. At the end of this period, 200 ml of ethyl acetate was added to the reaction mixture and the organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. The evaporation residue thus obtained was subjected to column chromatography on silica gel, using a 9:1 volumetric mixture of toluene and ethyl acetate as eluent to give 4.9 g of the title compound as an oil.

NMR spectrum (CDCl3) 6 ppm:

3.67 (2H, singlet),

4.05 (2H, triplet, J = 4.2 Hz),

4.29 (2H, triplet, J = 4.2 Hz),

7.10 - 7.40 (4H, multiplet).

Mass spectrum (CI, m/z): 212 (M<+>+1), 176.

Synthesis 2

3-(2-fluorobenzyl)-5.6-dihydro-1.4,2-dioxazine

A procedure similar to that described in Synthesis 1 was repeated, except that an equivalent amount of o-fluorophenylacetic acid was used instead of o-chlorophenylacetic acid, to give the title compound as a colorless oil in 45% yield.

Mass spectrum (CI, m/z): 196 (M<+>+1), 109.

Synthesis 3

3 -( 2. 6- difluorobenzyl)- 5. 6- dihydro- 1. 4. 2- dioxazine

A procedure similar to that described in Synthesis 1 was repeated, except that an equivalent amount of 2,6-difluorophenylacetic acid was used instead of o-chlorophenylacetic acid, to give the title compound as a colorless oil in 45% yield .

NMR spectrum (CDCl3) 6 ppm:

3.61 (2H, singlet),

4.04 (2H, triplet, J = 4.1 Hz),

4.30 (2H, triplet, J = 4.1 Hz),

6.80 - 7.30 (4H, multiplet).

Mass spectrum (CI, m/z): 214 (M<+>+1), 127.

Synthesis 4

2- Chlorobenzyl cyclopropyl ketone

10 mL of anhydrous diethyl ether was added to 0.45 g (18.5 mmol) of metallic magnesium, and then a solution of 2.0 mL (15.4 mmol) of 2-chlorobenzyl bromide in 10 mL of diethyl ether was slowly added dropwise to the resulting mixture , while stirring. The mixture was then stirred at room temperature for 1 hour. The resulting solution was slowly added dropwise to a solution of 1.1 ml of cyclopropyl cyanide in 10 ml of diethyl ether over a period of 30 minutes and then the mixture was stirred at room temperature for 2 hours. At the end of this time, a saturated aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was stirred at room temperature for 15 minutes.

200 ml of ethyl acetate was then added to the reaction mixture and the organic layer was separated, washed with water, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous sodium sulfate. Loose-

the solvent was then removed by distillation under reduced pressure. The evaporation residue thus obtained was subjected to column chromatography on silica gel, using a 9:1 volumetric mixture of toluene and ethyl acetate as eluent to give 2.0 g of the title compound as a colorless oil.

IR spectrum (thin film) v^^g cm"1:

1695.

NMR spectrum (CDCl 3 ) 6 ppm:

0.86 - 0.92 (2H, multiplet),

1.06 - 1.12 (2H, multiplet),

1.96 - 2.02 (1H, multiplet),

3.98 (2H, singlet),

7.10 - 7.50 (4H, multiplet).

Mass spectrum (CI, m/z): 195 (M<+>+1), 159.

Synthesis 5

1-(2-fluorophenyl)-2-pentanone

A procedure similar to that described in Synthesis 4 was repeated, except that equivalent amounts of 2-fluorobenzyl bromide and butyl cyanide were used instead of 2-chlorobenzyl bromide and cyclopropyl cyanide, to give the title compound as a colorless oil in a yield of 3 6%.

NMR spectrum (CDCl3) <5 ppm:

0.91 (3H, triplet, J = 8.0 Hz),

1.52 - 1.73 (2H, multiplet),

2.45 (2H, triplet, J = 8.0 Hz),

3.70 (2H, singlet),

7.00 - 7.30 (4H, multiplet).

Mass spectrum (CI, m/z): 181 (M<+>+1), 109.

Synthesis 6

1-(2-fluorophenyl)-2-hexanone

A procedure similar to that described in Synthesis 4 was repeated, except that equivalent amounts of 2-fluorobenzyl bromide and pentyl cyanide were used instead of 2-chlorobenzyl bromide and cyclopropyl cyanide, to give the title compound as a colorless oil in a yield of 46 %.

NMR spectrum (CDCl3) 6 ppm:

0.90 (3H, triplet, J = 8.00 Hz),

1.20 - 1.39 (2H, multiplet),

1.50 - 1.65 (2H, multiplet),

2.50 (2H, triplet, J = 8.0 Hz),

3.70 (2H, singlet),

7.00 - 7.30 (4H, multiplet).

Mass spectrum (CI, m/z): 195 (M<+>+1), 109.

Synthesis 7

1-(2-fluorophenyl)-3,3-dimethyl-2-butanone

A procedure similar to that described in Synthesis 4 was repeated, except that equivalent amounts of 2-fluorobenzyl bromide and tert-butyl cyanide were used instead of 2-chlorobenzyl bromide and cyclopropyl cyanide, to give the title compound as a colorless oil in a yield of 42%.

NMR spectrum (CDCl3) 6 ppm:

1.25 (9H, singlet),

3.80 (2H, singlet),

7.00 - 7.30 (4H, multiplet).

Mass spectrum (CI, m/z): 195 (M<+>+1), 109.

Synthesis 8

Cyclopropyl-2-fluorobenzyl ketone

A procedure similar to that described in Synthesis 4 was repeated, except that equivalent amounts of 2-fluorobenzyl bromide and cyclopropyl cyanide were used instead of 2-chlorobenzyl bromide and cyclopropyl cyanide, to give the title compound as a colorless oil in a yield of 70 %.

NMR spectrum (CDCl3) 6 ppm:

0.82 - 0.98 (2H, multiplet),

1.03 - 1.17 (2H, multiplet),

1.92 - 2.06 (1H, multiplet),

3, 86 (2H, singlet),

7.10 - 7.30 (4H, multiplet).

Mass spectrum (Cl, m/z): 179 (M<+>+1).

Synthesis 9

1-(2-fluorophenyl)-2-butanone

9(a) 1-(2-Fluorophenyl)-2-nitro-1-butene

30 mL of acetic acid was added to 4.73 g (38.11 mmol) of 2-fluorobenzaldehyde, 4.41 g (49.49 mmol) of nitropropane, and 3.23 g (41.90 mmol) of ammonium acetate, and the resulting mixture was heated under reflux and stirring for 4 hours. At the end of this period, the reaction mixture was cooled to room temperature, neutralized with an aqueous solution of sodium bicarbonate and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then xylene was added to the solution. The mixture was concentrated by evaporation under reduced pressure to give 7.4 g of the title compound as a pale yellow oil.

NMR spectrum (CDCl3) 6 ppm:

1.25 (3H, triplet, J = 6.5 Hz),

2.80 (2H, quartet, J = 6.5 Hz),

7.00 - 7.60 (4H, multiplet),

8, 03 (1H, singlet) .

Mass spectrum (CI, m/z): 196 (M<+>+1), 149.

9(b) 1-(2-Fluorophenyl)-2-butanone

100 ml of 90% (v/v) aqueous acetic acid was added to 7.4 g of 1-(2-fluorophenyl)-2-nitro-1-butene [prepared as described in step (a) above] and then 12 .11 g (190 mmol) of zinc powder added portionwise to the resulting mixture, while heating. The mixture was then heated under reflux and stirring for 4 hours. At the end of this period, the reaction mixture was left overnight, and then the crystals that had precipitated were filtered off and washed with toluene. The filtrate was combined with the toluene used for washing, and the mixture was concentrated by evaporation under reduced pressure. The evaporation residue thus obtained was subjected to column chromatography with silica gel, using toluene as eluent, to give 1.85 g of the title compound in the form of a light brown oil.

NMR spectrum (CDCl3) 6 ppm:

1.05 (3H, triplet, J = 7.0 Hz),

2.53 (2H, quartet, J = 7.0 Hz),

3.73 (2H, singlet),

7.00 - 7.40 (4H, multiplet).

Mass spectrum (CI, m/z): 167 (M<+>+1), 109.

Synthesis 10

1-(2-Chlorophenyl)-2-propanone

Following a procedure similar to that described in Synthesis 9, except that equivalent amounts of 2-chlorobenzaldehyde and nitroethane were used instead of 2-fluorobenzaldehyde and nitropropane, the title compound was obtained as a brown oil in 27% yield .

NMR spectrum (CDCl 3 ) 6 ppm:

2.20 (3H, singlet),

3.85 (2H, singlet),

7.15 - 7.45 (4H, multiplet).

Mass spectrum (CI, m/z): 169 (M<+>+1), 125.

Synthesis 11

1-(2-chlorophenyl)-2-butanone

Following a procedure similar to that described in Synthesis 9, except that an equivalent amount of 2-chlorobenzaldehyde was used instead of 2-fluorobenzaldehyde, the title compound was obtained as a light brown oil in 17% yield.

Mass spectrum (CI, m/z): 183 (M<+>+1), 125.

Synthesis 12

1-(2-chlorophenyl)-2-heptanone

Following a procedure similar to that described in Synthesis 9, except that equivalent amounts of 2-chlorobenzaldehyde and nitrohexane were used instead of 2-fluorobenzaldehyde and nitropropane, the title compound was obtained as a pale yellow oil in 17% yield .

NMR spectrum (CDCl3) 6 ppm:

0.90 (3H, triplet, J = 8.0 Hz),

1.20 - 1.40 (4H, multiplet),

1.50 - 1.70 (2H, multiplet),

2.50 (2H, triplet, J = 10.0 Hz),

3.80 (2H, singlet),

7.20 - 7.60 (4H, multiplet).

Mass spectrum (CI, m/z): 225 (M<+>+1), 125.

Synthesis 13

Cyclobutyl-2-fluorobenzyl ketone

20 ml of anhydrous diethyl ether was added to 1.06 g (44 mmol) of metallic magnesium, and then a solution of 7.56 g (40 mmol) of 2-fluorobenzyl bromide in 10 ml of diethyl ether was slowly added dropwise to the resulting mixture, with stirring. The mixture was then stirred at room temperature for 1 hour. The resulting solution was slowly added dropwise to a solution of 4.74 g (40 mmol) of cyclobutanecarbonyl in 30 mL of tetrahydrofuran, while cooling in a dry methanol ice bath, over a period of 2 hours, and the mixture was allowed to reflux to room temperature, with stirring, over a period of 2 hours. At the end of this period, 100 ml of water and 150 ml of diethyl were added to the reaction mixture, and the organic layer was separated, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The evaporation residue that thus appeared was subjected to column chromatography with silica gel, using a 9

: 1 volumetric mixture of toluene and hexane as eluent, to give 2.97 g of the title compound as a pale yellow oil.

NMR spectrum (CDCl3) 6 ppm:

1.65 - 2.40 (6H, multiplet),

3.31 - 3.48 (1H, multiplet),

3, 67 (2H, singlet),

7.00 - 7.30 (4H, multiplet).

Mass spectrum (CI, m/z): 193 (M<+>+1), 137.

Synthesis 14

5-chloro-1-(2-chlorophenyl)-2-pentanone

Following a procedure similar to that described in Synthesis 13, except that equivalent amounts of 2-chlorobenzyl bromide and 4-chlorobutyryl chloride were used in place of 2-fluorobenzyl bromide and cyclobutanecarbonyl chloride, the title compound was obtained as a yellow oil in a yield of 79%.

NMR spectrum (CDCl3) 6 ppm:

1.96 - 2.15 (2H, multiplet),

2.69 (2H, triplet, J = 7.7 Hz),

3.56 (2H, triplet, J = 7.7 Hz),

3.86 (2H, singlet),

7.10 - 7.50 (4H, multiplet).

Synthesis 15

1-(2-chlorophenyl)-3.3,3-trifluoro-2-propanone

10 mL of anhydrous diethyl ether was added to 0.9 g (37.0 mmol) of metallic magnesium, and then a solution of 3.9 mL (30.8 mmol) of 2-chlorobenzyl chloride in 10 mL of diethyl ether was slowly added dropwise to the resulting mixture , with vigorous stirring, over a period of 30 minutes. The mixture was then stirred at room temperature for 1 hour. The resulting solution was slowly added dropwise to a solution of 4.3 mL (30.8 mmol) of trifluoroacetic anhydride in 40 mL of tetrahydrofuran, while cooling to ca. -70°C, and then the mixture was allowed to return to room temperature, with stirring, over a period of approx. 1 hour. After this, the mixture was left overnight. At the end of this time, 200 mL of ethyl acetate was added to the resulting reaction mixture, and the organic layer was separated, washed with 1N aqueous hydrochloric acid and with a saturated aqueous solution of sodium chloride, in that order, dried over anhydrous sodium sulfate, and concentrated with of evaporation under reduced pressure. The evaporation residue thus obtained was subjected to silica gel column chromatography, using a 10:2 volumetric mixture of toluene and ethyl acetate as eluent, to give 5.7 g of the title compound as a yellow oil.

NMR spectrum (CDCl 3 ) 5 ppm:

4.16 (2H, singlet),

7.10 - 7.50 (4H, multiplet).

Mass spectrum (CI, m/z): 223 (M<+>+1), 125.

Synthesis 16

2 - chloro- or trifluoroacetyl benzyl bromide

2.0 g (9.0 mmol) of 1-(2-chlorophenyl)-3,3,3-trifluoro-2-propanone was dissolved in 30 ml of carbon tetrachloride and then 0.46 ml (0.9 mmol) of bromine was added the solution, which was then stirred at room temperature for 10 hours. At the end of this period, a sodium hydrogen sulphite was added to the reaction mixture and the mixture was stirred at room temperature for 15 minutes, after which the insoluble matter was removed by filtration. The filtrate was concentrated by evaporation under reduced pressure and the residue was subjected to silica gel column chromatography, using a 10:2 volumetric mixture of toluene and ethyl acetate as eluent, to give 0.87 g of the title compound as a yellow oil.

NMR spectrum (CDCl3) 6 ppm:

6.39 (1H, singlet),

7.30 - 7.70 (4H, multiplet).

Mass spectrum (CI, m/z): 302 (M<+>+2), 300 (M<+>), 221.

Synthesis 17

2-chloro-or-(4-chlorobutyryl)benzyl bromide

Following a procedure similar to that described in Synthesis 16, except that an equivalent amount of 1-(2-chlorophenyl)-5-chloro-2-pentanone was used in place of 1-(2-chlorophenyl)-3 ,3,3-trifluoro-2-propanone, the title compound appeared in the form of a yellow oil with a yield of 72%.

NMR spectrum (CDCl3) 5 ppm:

2.01 - 2.14 (2H, multiplet),

2.40 - 2.90 (2H, multiplet),

3.49 - 3.61 (2H, multiplet),

5.98 (1H, singlet),

7.20 - 7.60 (4H, multiplet).

Mass spectrum (CI, m/z): 311 (M<+>+1), 231.

Synthesis 18

2-chloro-Q'-(5,6-dihydro-1,4,2-dioxazin-3-yl)benzyl bromide

4.0 g (19.0 mmol) of 3-(2-chlorobenzyl)-5,6-dihydro-1,4,2-dioxazine (prepared as described in synthesis 1) was dissolved in 40 ml of carbon tetrachloride and then 4.1 g (23 mmol) of N-bromosuccinimide and 0.2 g of benzoyl peroxide were added to the solution, which was then stirred, under heating, for 8 hours. At the end of this period, 100 ml of ethyl acetate and 100 ml of hexane were added to the solution and the mixture was stirred at room temperature for 30 minutes. The insoluble material was then removed by filtration. The filtrate

was concentrated by evaporation under reduced pressure to give 4.8 g of the title compound as a yellow oil.

Mass spectrum (CI, m/z): 292 (M<+>+3), 290 (M<+>+1), 212.

Synthesis 19

2-fluoro-α:-(5,6-dihydro-l.4,2-dioxazin-3-yl)benzyl bromide

Following a procedure similar to that described in Synthesis 18, except that an equivalent amount of 3-(2-fluorobenzyl)-5,6-dihydro-1,4,2-dioxazine

(prepared as described in synthesis 2) was used instead of 3-(2-chlorobenzyl)-5,6-dihydro-1,4,2-dioxazine, the title compound appeared as a red oil in a yield of 98%.

Mass spectrum (CI, m/z): 276 (M<+>+3), 194.

Synthesis 20

2. 6- difluoro- a-(5. 6- dihydro-1, 4. 2- dioxazin-3- yl) benzyl bromide

Following a procedure similar to that described in Synthesis 18, except that an equivalent amount of 3-(2,6-difluorobenzyl)-5,6-dihydro-1,4,2-dioxazine (prepared as described in Synthesis 3) was used instead of 3-(2-chlorobenzyl)-5,6-dihydro-1,4,2-dioxazine, the title compound appeared in the form of a red oil with a yield of 57%.

Mass spectrum (CI, m/z): 294 (M<+>+3), 214.

Synthesis 21

2-chloro-α-cyclopropylcarbonylbenzylbromide

Following a procedure similar to that described in Synthesis 18, except that an equivalent amount of 2-chlorobenzylcyclopropylketone (prepared as described in Synthesis 4) was used in place of 3-(2-chlorobenzyl)-5,6-dihydro -1,4,2-dioxazine, the title compound appeared in the form of a red oil with a yield of 83%.

NMR spectrum (CDCl3) 5 ppm:

0.80 - 1.20 (4H, multiplet),

2.04 - 2.16 (1H, multiplet),

6.18 (1H, singlet),

7.20 - 7.60 (4H, multiplet).

Mass spectrum (CI, m/z): 275 (M<+>+3), 193.

Synthesis 22

2-chlorobenzyl-4-fluorophenyl ketone

Following a procedure similar to that described in Synthesis 13, except that equivalent amounts of 2-chlorobenzyl bromide and 4-fluorobenzoyl chloride were used instead of 2-fluorobenzyl bromide and cyclobutanecarbonyl chloride, the title compound was obtained as a colorless powder in a yield of 34%.

NMR spectrum (CDCl 3 ) 6 ppm:

4.40 (2H, singlet) ,

7.10 - 7.45 (6H, multiplet)

8.04 - 8.10 (2H, multiplet).

Mass spectrum (CI, m/z): 249 (M<+>+1), 213.

Synthesis 23

2- fluorobenzyl isopropyl ketone

Following a procedure similar to that described in Synthesis 4, except that equivalent amounts of 2-fluorobenzyl bromide and isobutyronitrile were used instead of 2-chlorobenzyl bromide and cyclopropyl cyanide, the title compound was obtained as a colorless oil in a yield of 25%.

NMR spectrum (CDCl3) 6 ppm:

1.15 (6H, doublet, J = 7.5 Hz),

2.75 (1H, septet, J = 7.5 Hz),

3.78 (2H, singlet),

6.97 - 7.30 (4H, multiplet).

Mass spectrum (CI, m/z): 181 (M<+>+1), 109.

Synthesis 24

Hydrochloric acid 2- nitro- 4. 5. 6. 7- tetrahydrothieno f3, 2- cl - pyridine

24( a) 5- Acetyl- 4. 5. 6. 7- tetrahydrothieno\ 3 . 2-clpyridine 35.1 g (200 mmol) hydrochloric acid 4,5,6,7-tetrahydrothieno-[3,2-c]pyridine and 38.57 g (200 mmol) 28% (w/v) sodium methoxide in methanol were added to 200 ml of ethanol,

and the resulting mixture was stirred at room temperature for 1 hour. The inorganic salt thus precipitated was filtered off and the filtrate was concentrated to dryness by evaporation under reduced pressure. 50 ml of acetic anhydride was added at once to the evaporation residue, below

stirring, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated to dryness by evaporation under reduced pressure, and the evaporation residue thus obtained was

subjected to silica gel column chromatography, using a 6:4 volumetric mixture of toluene and ethyl acetate as eluent, to give 29.32 g of the title compound as a yellow oil. 24 ( b) 5- acetyl- 2- nitro- 4. 5. 6. 7- tetrahydrothieno \ 3 . 2-clpyridine 20 ml of acetic anhydride solution containing 5.43 g (30 mmol) of 5-acetyl-4,5,6,7-tetrahydrothieno[3,2-c]-pyridine [prepared as described in step (a) of the preceding] was added dropwise at 10 - 18°C over a period of 1 hour to 30 ml of acetic acid solution containing 4.2 g (60 mmol) of 90% fuming nitric acid, and the mixture was then stirred at a temperature not exceeding 18° C for 1 hour. The reaction mixture was then poured into ice water and extracted with methylene chloride. The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate and with water, in that order, and dried over aqueous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting evaporation residue was crystallized from a mixture of hexane and toluene to give 4.46 g of the title compound as yellow crystals.

NMR spectrum (CDCl 3 ) 6 ppm:

2.19 & 2.21 (together 3H, each singlet),

2.82 - 3.05 (2H, multiplet),

3.80 - 3.95 (together 2H, each triplet, J = 5.7 Hz), 4.55 & 4.66 (together 2H, each singlet),

7.66 (1H, singlet).

Mass spectrum (Cl, m/z): 227 (M<+>+1).

24( c) Hydrochloric acid 2- nitro- 4, 5. 6, 7- tetrahydrothienof3, 2- cl - pyridine

2.38 g (10.53 mmol) of 5-acetyl-2-nitro-4,5,6,7-tetrahydrothieno[3,2-c]pyridine [prepared as described in step (b) above] was heated under reflux for 2 hours in 60 ml of 10% (w/v) aqueous hydrochloric acid. The reaction mixture was then concentrated to dryness by evaporation under reduced pressure to give 2.19 g of the title compound as brown crystals.

NMR spectrum (CD3OD) 6 ppm:

3.22 (2H, triplet, J = 6.2 Hz),

3.60 (2H, triplet, J = 6.2 Hz),

4.31 (2H, singlet),

7.87 (1H, singlet).

Mass spectrum (CI, m/z): 185 (M<+>+1).

Synthesis 25

4, 5, 6, 7-tetrahydrofuro[ 3 , 2-cl pyridine

3.7 g (46 mmol) of 37% aqueous formaldehyde solution was added dropwise at room temperature to 5.1 g (46 mmol) of 2-furylethylamine [the compound is described, for example, in Brit., J. Pharmacol., 9, 376 (1954)] , and the resulting mixture was stirred for approx. 15 minutes, after which it was extracted with diethyl ether. The organic extract was washed with water and dried over anhydrous sodium sulfate and then the diethyl ether was removed by distillation under reduced pressure. 5 ml of dimethylformamide was added to the evaporation residue and the resulting solution was added dropwise to 15 ml of dimethylformamide containing 3.6 g (100 mmol) of dry hydrochloric acid at room temperature. The resulting mixture was then stirred for 3 hours. At the end of this period, most of the dimethylformamide was removed by distillation under reduced pressure, and then water and a 0.1 N aqueous solution of sodium hydroxide were added to the distillation residue to adjust its pH to a value of about 11. The mixture was then extracted with chloroform. The organic extract was washed with water and dried over anhydrous sodium sulfate. The chloroform was then removed by evaporation under reduced pressure, and the resulting evaporation residue was purified by silica gel column chromatography, using a 50:1 volumetric mixture of chloroform and methanol as

eluent, to give the title compound as a brown oil in 27% yield.

NMR spectrum (CDCl3) 5 ppm:

3.10 - 3.20 (4H, multiplet),

3.70 - 3.80 (2H, multiplet),

6.20 (1H, singlet),

7.27 (1H, singlet).

Mass spectrum (CI, m/z): 124 (M<+>+1).

Synthesis 26

2- Fluorobenzyl- 2- fluorocyclopropyl ketone

A procedure similar to that described in Example 13 was repeated, except that an equivalent amount of 2-fluorocyclopropylcarbonyl chloride was used in place of cyclobutylcarbonyl chloride to give the title compound as a colorless oil in 27% yield

NMR spectrum (CDCl3) 6 ppm:

1.38 - 1.58 (2H, multiplet),

2.34 - 2.56 (1H, multiplet),

3.90 (2H, singlet),

4.54 - 4.61 Sc 4.86 - 4.93 (together 1H, each multiplet),

7.05 - 7.35 (4H, multiplet).

Mass spectrum (CI, m/z): 197 (M<+>+1), 109.

Synthesis 27 2 - Fluorobenzyl - or - ( 2 - fluorocyclopropylcarbonyl) benzyl bromide A procedure similar to that described in Synthesis 18 was repeated, except that an equivalent amount of 2-fluorobenzyl-2-fluorocyclopropyl ketone was used in place of 3-( 2-chlorobenzyl)-5,6-dihydro-1,4,2-dioxazine, to give the title compound as a colorless oil in 76% yield

NMR spectrum (CDCl3) 6 ppm:

1.44 - 1.73 (2H, multiplet),

2.54 - 2.76 (1H, multiplet),

4.54 - 4.68 & 4.85 - 4.99 (together 1H, each

multiplet),

5.93 (1H, singlet),

7.05 - 7.60 (4H, multiplet).

Mass spectrum (CI, m/z): 277 (M<+>+2), 275 (M<+>), 195.

Claims (30)

1. Chemical compound, characterized in that it has the formula (I): in which R<1>is a hydrogen atom or a halogen atom; R<2>is an alkanoyl group having from 1 to 10 carbon atoms, a halogen-substituted alkanoyl group having from 2 to 10 carbon atoms, a cycloalkylcarbonyl group having from 4 to 8 carbon atoms, a halogen-substituted cycloalkylcarbonyl group having from 4 to 8 carbon atoms, a halogen-substituted benzoyl group or a 5,6-dihydro-1,4,2-dioxazin-3-yl group, R is a hydrogen atom, a hydroxy group, an alkoxy group with from 1 to 4 carbon atoms, an alkanoyloxy group with from 1 to 18 carbon atoms, an alkanoyloxyalkyl group in which the alkanoyl part has from 1 to 6 carbon atoms and the alkoxy part has from 1 to 4 carbon atoms, an alkoxycarbonyloxy group with from 2 to 5 carbon atoms, an amino group, an alkanoylamino group of from 1 to 10 carbon atoms or a nitro group, Y is an oxygen or sulfur atom, n is an integer of 1 or 2, and when n is 2, the groups represented by R<1> can be the same or different from each other, and tautomers thereof, as well as pharmaceutically acceptable salts of the compounds of formula (I) and of the tautomers. 2. Chemical compound in accordance with claim 1, characterized in that the tautomer has the formula (la): wherein R<1>, R<2>, Y and n are as defined above and Z is an oxygen atom. 3. Chemical compound in accordance with one of claims 1 or 2, characterized in that R is an alkanoyl group having from 2 to 6 carbon atoms, a halogen-substituted alkanoyl group having from 2 to 6 carbon atoms, a cycloalkylcarbonyl group having from 4 to 7 carbon atoms, a halogen-substituted cycloalkylcarbonyl group having from 4 to 7 carbon atoms, a substituted benzoyl group with at least one fluoro substituent, or a 5,6-dihydro-1,4,2-dioxazin-3-yl group. 4. Compound according to any one of claims 1 to 3, characterized in that R3 denotes a hydrogen atom, an alkoxy group with from 1 to 4 carbon atoms, an alkanoyloxymethoxy group in which the alkanoyl part has from 1 to 5 carbon atoms, an alkanoyloxy group with from 1 to 18 carbon atoms, an alkoxycarbonyloxy group with from 2 to 5 carbon atoms, an amino group, an alkanoylamino group with from 1 to 10 carbon atoms. 5. Compound according to claim 1 or 2, characterized in that: R<1> denotes a halogen atom; R2 denotes an alkanoyl group having from 2 to 6 carbon atoms, a halogen-substituted alkanoyl group having from 2 to 6 carbon atoms, a cycloalkylcarbonyl group having from 4 to 7 carbon atoms, a halogen-substituted cycloalkylcarbonyl group having from 4 to 7 carbon atoms, a substituted benzoyl group with at least one fluorine substituent, or a 5,6-dihydro-1,4,2-dioxazin-3-yl group; R3 denotes a hydrogen atom, a hydroxy group, an alkoxy group with from 1 to 4 carbon atoms, an alkanoyloxymethoxy group in which the alkanoyl part has from 1 to 5 carbon atoms, an alkanoyloxy group with from 1 to 18 carbon atoms, an alkoxycarbonyloxy group with from 2 to 5 carbon atoms, an amino group or an alkanoylamino group having from 1 to 10 carbon atoms; and Y represents an oxygen or sulfur atom. 6. Connection according to any of the preceding claims, characterized in that R<2> denotes an alkanoyl group with from 2 to 6 carbon atoms, a substituted alkanoyl group having from 2 to 6 carbon atoms and which is substituted with at least one fluorine atom, a cycloalkylcarbonyl group with from 4 to 7 carbon atoms or a substituted cycloalkylcarbonyl group which is substituted with at least one fluorine atom. 7. Connection according to any of the preceding claims, characterized in that R<3> denotes a hydrogen atom, a methoxy group, an ethoxy group, a t-butoxy group, an alkanoyloxymethoxy group in which the alkanoyl part has from 1 to 5 carbon atoms, an alkanoyloxy group with from 1 to 12 carbon atoms, an alkoxycarbonyloxy group with from 2 to 5 carbon atoms, an amino group or a t-butoxycarbonylamino group. 8. Compound according to claim 1 or 2, characterized in that: R<1> denotes a halogen atom; R2 denotes an alkanoyl group having from 2 to 6 carbon atoms, a halogen-substituted alkanoyl group having from 2 to 6 carbon atoms, a cycloalkylcarbonyl group having from 4 to 7 carbon atoms, a halogen-substituted cycloalkylcarbonyl group having from 4 to 7 carbon atoms, a halogen-substituted benzoyl group with at least one fluorine substituent, or a 5,6-dihydro-1,4,2-dioxazin-3-yl group; R3 denotes a hydrogen atom, a methoxy group, an ethoxy group, a t-butoxy group, an alkanoyloxymethoxy group in which the alkanoyl part has from 1 to 5 carbon atoms, an alkanoyloxy group with from 1 to 12 carbon atoms, an alkoxycarbonyloxy group with from 2 to 5 carbon atoms, an amino group or a t -butoxycarbonylamino group; and Y represents an oxygen or sulfur atom. 9. A connection according to any of the preceding claims, characterized in that R 3 denotes a hydrogen atom, a pivaloyloxymethoxy group, an alkanoyloxy group having from 2 to 10 carbon atoms, or an alkoxycarbonyloxy group having from 2 to 5 carbon atoms. 10. Connection according to any of the preceding claims, characterized in that Y denotes a sulfur atom. 11. Compound according to claim 1 or 2, characterized in that: R<1> denotes a halogen atom; R<2>denotes an alkanoyl group with from 2 to 6 carbon atoms, an alkanoyl group having from 2 to 6 carbon atoms and which is substituted with at least one fluorine atom, a cycloalkylcarbonyl group with from 4 to 7 carbon atoms, or a cycloalkylcarbonyl group which is substituted with at least one fluorine atom; R3 denotes a hydrogen atom, a pivaloyloxymethoxy group, an alkanoyloxy group with from 2 to 10 carbon atoms or an alkoxycarbonyloxy group with from 2 to 5 carbon atoms; and Y denotes a sulfur atom. 12. Connection according to any of the preceding claims, characterized in that R<1> denotes a fluorine or chlorine atom. 13. A connection according to any of the preceding claims, characterized in that R<2> denotes an acetyl group, a propionyl group, an acetyl group or propionyl group which is substituted by at least one fluorine atom, a cyclopropylcarbonyl group, a cyclobutylcarbonyl group or a cyclopropylcarbonyl or cyclobutylcarbonyl group which is substituted by at least one fluorine atom. 14. A connection according to any of the preceding claims, characterized in that R3 denotes a hydrogen atom, a pivaloyloxymethoxy group, an alkanoyloxy group with from 2 to 6 carbon atoms or an alkoxycarbonyloxy group with from 2 to 5 carbon atoms. 15. Compound according to claim 1 or 2, characterized in that: R<1> denotes a fluorine or chlorine atom; R 2 denotes an acetyl group, a propionyl group, an acetyl or propionyl group which is substituted by at least one fluorine atom, a cyclopropylcarbonyl group, a cyclobutylcarbonyl group or a cyclopropylcarbonyl or cyclobutylcarbonyl group which is substituted by at least one fluorine atom; R3 denotes a hydrogen atom, a pivaloyloxymethoxy group, an alkanoyloxy group with from 2 to 6 carbon atoms or an alkoxycarbonyloxy group with from 2 to 5 carbon atoms; and Y denotes a sulfur atom. 16. A connection according to any of the preceding claims, characterized vedatnerl. 17. Compound according to claim 1, characterized in that this is 5-(2-fluoro-α-propionylbenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine or a pharmaceutically acceptable salt thereof. 18. Compound according to claim 1, characterized in that this is 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine or a pharmaceutically acceptable salt thereof. 19. Compound according to claim 1, characterized in that this is 5-(2-chloro-α-cyclopropylcarbonylbenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine or a pharmaceutically acceptable salt thereof. 20. Compound according to claim 1, characterized in that this is 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno-[3,2-c]pyridine or a pharmaceutically acceptable salt hence. 21. Compound according to claim 1, characterized in that this is 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-propionyloxy-4,5,6,7-tetra hydrothieno[3,2-c]pyridine or a pharmaceutically acceptable salt thereof. 22. Compound according to claim 1, characterized in that this is 2-butyryloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4, 5, 6,7-tetrahydrothieno[3,2-c]pyridine or a pharmaceutically acceptable salt hence. 23. Compound according to claim 1, characterized in that this is 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-pivaloyloxy-4, 5, 6,7-tetrahydrothieno[3,2-c]pyridine or a pharmaceutically acceptable salt hence. 24. Compound according to claim 1, characterized in that this is 2-t-butoxycarbonyloxy-5-(α-cyclopropylcarbonyl 1-2-fluorobenzyl)-4, 5,6,7-tetrahydrothieno[3,2-c]pyridine or a pharmaceutical acceptable salt thereof. 25. Compound according to claim 1, characterized in that this is 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-pivaloyloxymethoxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine or a pharmaceutically acceptable salt thereof . 26. Compound according to claim 1, characterized in that this is 5-(2-chloro-a-cyclopropylcarbonylbenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro-thieno[3,2-c]pyridine or a tautomer thereof or a pharmaceutically acceptable salt thereof. 27. Compound according to claim 1, characterized in that this is 5-(2-fluoro-a-propionylbenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno [3, 2-c]-pyridine or a tautomer thereof or a pharmaceutically acceptable salt thereof. 28. Compound according to claim 1, characterized in that this is 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4, 5,6,7, 7α-hexahydro-thieno[3,2-c] pyridine or a tautomer thereof or a pharmaceutically acceptable salt thereof. 29. Compound according to claim 1, characterized in that this is 5-[a-(2-fluoro-cyclopropylcarbonyl-2-fluorobenzyl]-2-oxo-2,4,5,6,7,7a-hexa-hydrothieno[3, 2-c]pyridine or a tautomer thereof or a pharmaceutically acceptable salt thereof. 30. Pharmaceutical preparation, characterized in that it contains as active ingredient a compound according to any of the preceding claims.